Indoles and their therapeutic use

ABSTRACT

Compounds of the invention are ligands of the CRTH2 receptor, useful inter alia for treatment of inflammatory conditions.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation application of co-pending applicationSer. No. 12/746,104; filed Nov. 22, 2010; which is a National StageApplication of International Application Number PCT/GB2008/004107, filedDec. 12, 2008; which claims priority to Great Britain Application Nos.0724429.6, filed Dec. 14, 2007; 0806083.2, filed Apr. 3, 2008; and0814910.6, filed Aug. 14, 2008; all of which are all incorporated hereinby reference in their entirety.

This invention relates to a class of indole compounds, which are ligandsof the CRTH2 receptor (Chemoattractant Receptor-homologous moleculeexpressed on T Helper cells type 2), and their use in the treatment ofdiseases responsive to modulation of CRTH2 receptor activity,principally diseases having a significant inflammatory component. Theinvention also relates to novel members of that class of ligands andpharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Mast cells are known to play an important role in allergic and immuneresponses through the release of a number of mediators, such ashistamine, leukotrienes, cytokines, prostaglandin D₂, etc (Boyce;Allergy Asthma Proc., 2004, 25, 27-30). Prostaglandin D₂ (PGD₂) is themajor metabolite produced by the action of cyclooxygenase on arachadonicacid by mast cells in response to allergen challenge (Lewis et al; J.Immunol., 1982, 129, 1627-1631). It has been shown that PGD₂ productionis increased in patients with systemic mastocytosis (Roberts; N. Engl.J. Med., 1980, 303, 1400-1404), allergic rhinitis (Naclerio et al; Am.Rev. Respir. Dis., 1983, 128, 597-602; Brown et al; Arch. Otolarynol.Head Neck Surg., 1987, 113, 179-183; Lebel et al; J. Allergy Clin.Immunol., 1988, 82, 869-877), bronchial asthma (Murray et al; N. Engl.J. Med., 1986, 315, 800-804; Liu et al; Am. Rev. Respir. Dis., 1990,142, 126-132; Wenzel et al; J. Allergy Clin. Immunol., 1991, 87,540-548), and urticaria (Heavey et al; J. Allergy Clin. Immunol., 1986,78, 458-461). PGD₂ mediates it effects through two receptors, the PGD₂(or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916)and the chemoattractant receptor-homologous molecule expressed on Th2(or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278-1289; Powell;Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185).Therefore, it has been postulated that agents that antagonise theeffects of PGD₂ at its receptors may have beneficial effects in a numberof disease states.

The CRTH2 receptor has been shown to be expressed on cell typesassociated with allergic inflammation, such as basophils, eosinophils,and Th2-type immune helper cells (Hirai et al; J. Exp. Med., 2001, 193,255-261). The CRTH2 receptor has been shown to mediate PGD₂-mediatedcell migration in these cell types (Hirai et al; J. Exp. Med., 2001,193, 255-261), and also to play a major role in neutrophil andeosinophil cell recruitment in a model of contact dermatitis (Takeshitaet al; Int. Immunol., 2004, 16, 947-959). Ramatroban{(3R)-3-[(4-fluorophenyl)sulphonylamino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoicacid}, a dual CRTH2 and thromboxane A₂ receptor antagonist, has beenshown to attenuate these responses (Sugimoto et al; J. Pharmacol. Exp.Ther., 2003, 305, 347-352; Takeshita et al; op. cit.). The potential ofPGD₂ both to enhance allergic inflammation and induce an inflammatoryresponse has been demonstrated in mice and rats. Transgenic mice overexpressing PGD₂ synthase exhibit an enhanced pulmonary eosinophilia andincreased levels of Th2 cytokines in response to allergen challenge(Fujitani et al, J. Immunol., 2002, 168, 443-449). In addition,exogenously administered CRTH2 agonists enhance the allergic response insensitised mice (Spik et al; J. Immunol., 2005, 174, 3703-3708). In ratsexogenously applied CRTH2 agonists cause a pulmonary eosinophilia but aDP agonist (BW 245C) or a TP agonist (I-BOP) showed no effect (Shirashiet al; J. Pharmacol. Exp Ther., 2005, 312, 954-960). These observationssuggest that CRTH2 antagonists may have valuable properties for thetreatment of diseases mediated by PGD₂.

In addition to Ramatroban a number of other CRTH2 antagonists have beendescribed. Examples include: indole acetic acids (WO2008/012511;WO2007/065684; WO2007/045867; WO2006/034419; WO2005/094816;WO2005/044260; WO2005/040114; WO2005/040112; GB2407318; WO2005/019171;WO2004/106302; WO2004/078719; WO2004/007451; WO2003/101981;WO2003/101961; WO2003/097598; WO2003/097042; WO2003/066047;WO2003/066046; WO2003/022813), indolizine acetic acids (WO2008/113965;WO2008/074966; WO2007/031747; WO2006/136859), pyrrole acetic acids(WO2007/144127; WO2006/063763), quinolines (WO2008/122784;WO2008/119917; WO2007/036743), tetrahydroquinolines (WO2006/091674;US2005/256158; WO2005/100321; WO2005/007094; WO2004/035543;WO2004/032848; EP1435356; EP1413306), phenoxyacetic acids(WO2007/062678; WO2007/062773; WO2006/125596; WO2006/125593;WO2006/056752; WO2005/115382; WO2005/105727; WO2005/018529;WO2004/089885; WO2004/089884) and phenylacetic acids (WO2004/058164).

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention provides indole derivatives of formula (I):

X is —SO₂— or *—SO₂NR³— wherein the bond marked with an asterisk isattached to Ar¹;

R¹ is hydrogen, fluoro, chloro, CN or CF₃;

R² is hydrogen, fluoro or chloro;

R³ is hydrogen, C₁-C₃alkyl or C₃-C₇cycloalkyl;

Ar¹ is phenyl or a 5- or 6-membered heteroaryl group selected fromfuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl, wherein the phenyl or heteroaryl groups are optionallysubstituted by one or more substituents independently selected fromfluoro, chloro, CN, C₃-C₇cycloalkyl, —O(C₁-C₄alkyl) or C₁-C₆alkyl, thelatter two groups being optionally substituted by one or more fluoroatoms;

Ar² is phenyl or 5- or 6-membered heteroaryl group selected frompyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl, wherein the phenyl or heteroaryl groups are optionallysubstituted by one or more substituents independently selected fromfluoro, chloro, CN, C₃-C₇cycloalkyl, —O(C₁-C₄alkyl) or C₁-C₆alkyl, thelatter two groups being optionally substituted by one or more fluoroatoms.

Compounds (I) with which the invention is concerned are CRTH2 receptorantagonists, but they may also have beneficial effects at otherprostanoid receptors, such as the PGD₂ receptor or the thromboxane A₂receptor.

Compounds of formula (I) above may be prepared or recovered in the formof salts, and in some cases as N-oxides, hydrates, and solvates thereof.Any reference herein, including the claims herein, to “compounds of theinvention”, “compounds with which the invention is concerned” or“compounds of formula (I)” and the like, includes reference to salts,particularly pharmaceutically acceptable salts, N-oxides, hydrates, andsolvates of such compounds.

The invention also includes (i) use of a compound with which theinvention is concerned in the manufacture of a medicament for use in thetreatment of conditions responsive to modulation of CRTH2 receptoractivity, and (ii) a method of treatment of conditions responsive tomodulation of CRTH2 receptor activity, comprising administering to apatient suffering such disease an effective amount of a compound withwhich the invention is concerned.

Examples of conditions responsive to modulation of CRTH2 receptoractivity include asthma, rhinitis, allergic airway syndrome, allergicrhinobronchitis, bronchitis, chronic obstructive pulmonary disease(COPD), nasal polyposis, sarcoidosis, farmer's lung, fibroid lung,cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis,Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementiacomplex, Huntington's disease, frontotemporal dementia, Lewy bodydementia, vascular dementia, Guillain-Barre syndrome, chronicdemyelinating polyradiculoneurophathy, multifocal motor neuropathy,plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis,cerebellar degeneration and encephalomyelitis, CNS trauma, migraine,stroke, rheumatoid arthritis, ankylosing spondylitis, Behçet's Disease,bursitis, carpal tunnel syndrome, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, dermatomyositis, Ehlers-Danlos Syndrome(EDS), fibromyalgia, myofascial pain, osteoarthritis (OA),osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactivearthritis), sarcoidosis, scleroderma, Sjogren's Syndrome, soft tissuedisease, Still's Disease, tendinitis, polyarteritis Nodossa, Wegener'sGranulomatosis, myositis (polymyositis dermatomyositis), gout,atherosclerosis, lupus erythematosus, systemic lupus erythematosus(SLE), type I diabetes, nephritic syndrome, glomerulonephritis, acuteand chronic renal failure, eosinophilia fascitis, hyper IgE syndrome,sepsis, septic shock, ischemic reperfusion injury in the heart,allograft rejection after transplantations, and graft versus hostdisease.

However, the compounds with which the invention is concerned areprimarily of value for the treatment of asthma, chronic obstructivepulmonary disease, rhinitis, allergic airway syndrome, or allergicrhinobronchitis. Psoriasis, atopic and non-atopic dermatitis Crohn'sdisease, ulcerative colitis, and irritable bowel disease are otherspecific conditions where the present compounds may have particularutility.

Another aspect of the invention is a pharmaceutical compositioncomprising a compound with which the invention is concerned in admixturewith a pharmaceutically acceptable carrier or excipient.

Terminology

As used herein, the term “(C_(a)-C_(b))alkyl” wherein a and b areintegers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms. Thus when a is 1 and b is 6, for example, theterm includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term “cycloalkyl” refers to a monocyclic saturatedcarbocyclic radical having from 3-8 carbon atoms and includes, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

As used herein the term “salt” includes base addition, acid addition andquaternary salts. Compounds of the invention which are acidic can formsalts, including pharmaceutically acceptable salts, with bases such asalkali metal hydroxides, for example sodium and potassium hydroxides;alkaline earth metal hydroxides, for example calcium, barium andmagnesium hydroxides; with organic bases, for exampleN-methyl-D-glucamine, choline tris(hydroxymethyl)aminomethane,L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.Specific salts with bases include the piperazine, ethanolamine,benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine,sodium, tromethamine and zinc salts. Those compounds of the inventionwhich are basic can form salts, including pharmaceutically acceptablesalts with inorganic acids, for example with hydrohalic acids such ashydrochloric or hydrobromic acids, sulphuric acid, nitric acid orphosphoric acid and the like, and with organic acids, for exampleacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric,methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic,glutamic, lactic and mandelic acids and the like. Where a compoundcontains a quaternary ammonium group acceptable counter-ions may be, forexample chlorides, bromides, sulfates, methanesulfonates,benzenesulfonates, toluenesulfonates (tosylates), napadisylates(naphthalene-1,5-disulfonates or naphthalene-1-(sulfonicacid)-5-sulfonates), edisylates (ethane-1,2-disulfonates orethane-1-(sulfonic acid)-2-sulfonates), isethionates2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates,tartrates, mesylates, maleates, malates, fumarates, succinates,xinafoates, p-acetamidobenzoates and the like; wherein the number ofquaternary ammonium species balances the pharmaceutically acceptablesalt such that the compound has no net charge.

Salts are discussed in the “Handbook of Pharmaceutical Salts.Properties, selection and use”, P. Heinrich Stahl & Camille G. Wermuth,Wiley-VCH, 2002.

The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Compounds with which the invention is concerned may exist in one or morestereoisomeric form, because of the presence of asymmetric atoms orrotational restrictions, and in such cases can exist as a number ofstereoisomers with R or S stereochemistry at each chiral centre or asatropisomers with R or S stereochemistry at each chiral axis. Theinvention includes all such enantiomers and diastereoisomers andmixtures thereof.

Use of prodrugs, such as esters, of compounds with which the inventionis concerned is also part of the invention. “Prodrug” means a compoundthat is convertible in vivo by metabolic means (for example, byhydrolysis, reduction or oxidation) to a compound of formula (I). Forexample an ester prodrug of a compound of formula (I) may be convertibleby hydrolysis in vivo to the parent molecule. Suitable esters ofcompounds of formula (I) are for example acetates, citrates, lactates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyl-tartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluene-sulphonates,cyclohexylsulphamates and quinates. Examples of ester prodrugs are thosedescribed by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. As usedin herein, references to the compounds of formula (I) are meant to alsoinclude the prodrug forms.

Structural Aspects of Compounds with which the Invention is Concerned

Subject to the proviso in the above definition of compounds with whichthe invention is concerned:

R¹ is hydrogen, fluoro, chloro, CN or CF₃ and R² is hydrogen, fluoro orchloro. In one particular subset of compounds of the invention R¹ isfluoro and R² is hydrogen. In another subset of compounds of theinvention R¹ is chloro and R² is hydrogen. All combinations of thepermitted substituents R¹ and R² are allowed.

Ar¹ is phenyl or 5- or 6-membered heteroaryl group selected fromfuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl. In some cases, Ar¹ is phenyl, thienyl, pyridinyl, pyrimidinylimidazolyl, isothiazolylor thiazolyl.

Ar² is phenyl or 5- or 6-membered heteroaryl. Examples of such ringsinclude phenyl, pyrrolyl, imidazolyl, furanyl, thienyl, oxazolyl,thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrazinyl,pyrimidinyl and pyridazinyl. In some cases ring Ar² is phenyl orpyridinyl.

In one particular subclass of compounds of the invention, X is *—SO₂NR³—wherein the bond marked with an asterisk is attached to Ar¹.

In some compounds of the invention, Ar¹ is phenyl and Ar² is selectedfrom pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyland pyrazinyl.

In some other compounds of the invention, Ar¹ selected from furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, phenyland Ar² is phenyl.

When ring Ar¹ is heteroaryl it may be selected from, for example,thienyl, pyridinyl, pyrimidinyl, thiazolyl, isothiazolyl and imidazolyl.

When ring Ar² is heteroaryl it may be selected from, for example,thienyl, pyridinyl, and pyrimidinyl.

Ar¹ and Ar² may be optionally be substituted by one or more substituentsindependently selected from fluoro, chloro, CN, C₃-C₇cycloalkyl such ascyclopropyl, O(C₁-C₄alkyl) such as methoxy, C₁-C₆alkyl such as methyl orthe latter two groups being optionally substituted by one or more fluoroatoms, as in the case of trifluormethoxy or trifluoromethyl. Currentlypreferred such substituents are chloro, fluoro, CN and methyl.

The radical Ar²SO₂— or Ar²N(R³)SO₂— may be in the meta- or para-positionof the ring Ar¹ relative to the point of attachment of Ar¹ to the restof the molecule.

However, currently it is preferred that the radicals Ar²SO₂— orAr²SO₂NR³— are in the ortho-position of the ring Ar¹ relative to thepoint of attachment of Ar¹ to the rest of the molecule.

Specific compounds of the invention include those of the Examplesherein.

Compositions

As mentioned above, the compounds with which the invention is concernedare CRTH2 receptor antagonists, and are useful in the treatment ofdiseases, which benefit from such modulation. Examples of such diseasesare referred to above, and include asthma, rhinitis, allergic airwaysyndrome, bronchitis and chronic obstructive pulmonary disease.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range will lie within the range of fromabout 0.001 mg to about 100 mg per kg body weight of a mammal, often0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, insingle or divided doses. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. Orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations, which may beused for the drug, are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

The drug may also be formulated for inhalation, for example as a nasalspray, or dry powder or aerosol inhalers. For delivery by inhalation,the active compound is preferably in the form of microparticles. Theymay be prepared by a variety of techniques, including spray-drying,freeze-drying and micronisation. Aerosol generation can be carried outusing, for example, pressure-driven jet atomizers or ultrasonicatomizers, preferably using propellant-driven metered aerosols orpropellant-free administration of micronized active compounds from, forexample, inhalation capsules or other “dry powder” delivery systems.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

Other compounds may be combined with compounds with which the inventionis concerned for the prevention and treatment of prostaglandin-mediateddiseases. Thus the present invention is also concerned withpharmaceutical compositions for preventing and treating PGD₂-mediateddiseases comprising a therapeutically effective amount of a compound ofthe invention and one or more other therapeutic agents. Suitabletherapeutic agents for a combination therapy with compounds of theinvention include, but are not limited to: (1) corticosteroids, such asfluticasone, ciclesonide or budesonide; (2) β2-adrenoreceptor agonists,such as salmeterol, indacaterol or formoterol; (3) leukotrienemodulators, for example leukotriene antagonists such as montelukast,zafirulast or pranlukast or leukotriene biosynthesis inhibitors such asZileuton or BAY-1005; (4) anticholinergic agents, for examplemuscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5)phosphodiesterase-IV (PDE-IV) inhibitors, such as roflumilast orcilomilast; (6) antihistamines, for example selective histamine-1 (H1)receptor antagonists, such as fexofenadine, citirizine, loratidine orastemizole; (7) antitussive agents, such as codeine or dextramorphan;(8) non-selective COX-1/COX-2 inhibitors, such as ibuprofen orketoprofen; (9) COX-2 inhibitors, such as celecoxib and rofecoxib; (10)VLA-4 antagonists, such as those described in WO97/03094 and WO97/02289;(11) TACE inhibitors and TNF-α inhibitors, for example anti-TNFmonoclonal antibodies, such as Remicade and CDP-870 and TNF receptorimmunoglobulin molecules, such as Enbrel; (12) inhibitors of matrixmetalloprotease, for example MMP12; (13) human neutrophil elastaseinhibitors, such as those described in WO2005/026124, WO2003/053930 andWO06/082412; (14) A2a agonists such as those described in EP1052264 andEP1241176 (15) A2b antagonists such as those described in WO2002/42298;(16) modulators of chemokine receptor function, for example antagonistsof CCR3 and CCR8; (17) compounds which modulate the action of otherprostanoid receptors, for example a thromboxane A₂ antagonist; and (18)agents that modulate Th2 function, such as PPAR agonists.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.

Synthesis

There are multiple synthetic strategies for the synthesis of thecompounds with which the present invention is concerned, but all rely onchemistry known to the synthetic organic chemist. Thus, compounds of theinvention can be synthesised according to procedures described in thestandard literature and are well-known to the one skilled in the art.Typical literature sources are “Advanced organic chemistry”, 4^(th)Edition (Wiley), J. March, “Comprehensive Organic Transformation”,2^(nd) Edition (Wiley), R. C. Larock, “Handbook of HeterocyclicChemistry”, 2^(nd) Edition (Pergamon), A. R. Katritzky, review articlessuch as found in “Synthesis”, “Acc. Chem. Res.”, “Chem. Rev.”, orprimary literature sources identified by standard literature searchesonline or from secondary sources such as “Chemical Abstracts” or“Beilstein”. The extensive literature relating to the synthesis ofindole compounds is especially relevant, of course.

It may be necessary to protect reactive functional groups (for example,hydroxy, amino, thio or carboxy) in intermediates used in thepreparation of compounds of formula (I) to avoid their unwantedparticipation in a reaction leading to the formation of compounds offormula (I). Conventional protecting groups, for example those describedby T. W. Greene and P. G. M. Wuts in “Protective groups in organicchemistry” John Wiley and Sons, 1999, may be used.

The compounds of the invention of formula (I) may be isolated in theform of their pharmaceutically acceptable salts, such as those describedpreviously herein above. The free acid form corresponding to isolatedsalts can be generated by acidification with a suitable acid such asacetic acid and hydrochloric acid and extraction of the liberated freeacid into an organic solvent followed by evaporation. The free acid formisolated in this manner can be further converted into anotherpharmaceutically acceptable salt by dissolution in an organic solventfollowed by addition of the appropriate base and subsequent evaporation,precipitation, or crystallisation.

Compounds of formula (Ia), wherein X, R¹, R², Ar¹ and Ar² are as definedfor formula (I) above, may conveniently be prepared by the reactionbetween an indole of formula (II), wherein E represents hydrogen oralkyl group, and an aldehyde of formula (III) (Scheme 1). The reactionis carried out under acidic reductive conditions, for example a mixtureof trifluoroacetic acid and triethylsilane. It is to be understood thatif the reaction is carried out on a protected form of (II) anappropriate deprotection step will be required to obtain the desiredcompound of the invention (Ia). Compounds of formula (II) arecommercially available or can be prepared by known methods (Kim et al;J. Heterocycl. Chem., 1981, 18, 1365-71; Forbes et al; Syn. Commun.,1996, 26, 745-754).

Intermediate compounds of formula (III), wherein X represents SO₂ group,may be prepared by the oxidation of compounds of formula (IV), with asuitable oxidising agent such as potassium peroxymonosulfate,meta-chloroperoxybenzoic acid or other well known oxidising agents(Scheme 2).

Compounds of formula (IV) may be prepared from compounds of formula (V),wherein T represents a chloro, bromo, or iodo atom, or atrifluoromethanesulfonyloxy group, by reaction with a thiol of formula(VI) in the presence of a suitable base such as potassium carbonate(Scheme 3). Alternatively, the reaction may be carried out in thepresence of a suitable catalyst, such astetrakis(triphenylphosphine)palladium(0) in a protic solvent such asethanol. Compounds of formula (V) and (VI) are commercially available orcan be prepared by known methods.

Alternatively, intermediate compounds of formula (III), wherein Xrepresents SO₂ group, may be prepared by reaction of compounds offormula (V) and (VII) (Scheme 4). The reaction may be carried out in asuitable solvent such as dimethyl sulfoxide, at temperatures rangingfrom room temperature to 150° C. Compounds of formula (VII) arecommercially available or can be prepared by known methods.

Intermediate compounds of formula (III), wherein X represents SO₂NR³group, may be prepared by the reaction between a compound of formula(VIII) and an amine of formula (IX) (Scheme 5). The reaction may becarried out in the presence of a suitable base (for example,triethylamine or diisopropylethylamine) and solvent (for example,dichloromethane or dichloroethane), at temperatures ranging from 0° C.to the reflux temperature of the solvent, preferably at about roomtemperature. Compounds of formula (VIII) and (IX) are commerciallyavailable or can be prepared by known methods.

EXAMPLES

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probespectrometer. Chemical shifts are expressed in ppm relative totetramethylsilane. The following abbreviations have been used: brs=broad singlet, s=singlet, d=doublet, dd=double doublet, t=triplet,q=quartet, m=multiplet.

Mass Spectrometry (LCMS) experiments to determine retention times andassociated mass ions were performed using the following methods:

Method A: experiments were performed on a Micromass Platform LCTspectrometer with positive ion electrospray and single wavelength UV 254nm detection using a Higgins Clipeus C18 5 μm 100×3.0 mm column and a 2mL/minute flow rate. The initial solvent system was 95% water containing0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formicacid (solvent B) for the first minute followed by a gradient up to 5%solvent A and 95% solvent B over the next 14 minutes. The final solventsystem was held constant for a further 2 minutes.

Method B: experiments were performed on a Micromass Platform LCspectrometer with positive and negative ion electrospray and ELS/Diodearray detection using a Phenomenex Luna C18(2) 30×4.6 mm column and a 2mL/minute flow rate. The solvent system was 95% solvent A and 5% solventB for the first 0.50 minutes followed by a gradient up to 5% solvent Aand 95% solvent B over the next 4 minutes. The final solvent system washeld constant for a further 0.50 minutes

Microwave experiments were carried out using a Personal Chemistry SmithSynthesizer™, which uses a single-mode resonator and dynamic fieldtuning, both of which give reproducibility and control. Temperaturesfrom 40-250° C. can be achieved, and pressures of up to 20 bars can bereached. Two types of vial are available for this processor, 0.5-2.0 mLand 2.0-5.0 mL.

Reverse-phase preparative HPLC purifications were carried out usingGenesis 7 micron C-18 bonded silica stationary phase in columns 10 cm inlength and 2 cm internal diameter. The mobile phase used was mixtures ofacetonitrile and water (both buffered with 0.1% v/v trifluoroacetic acidor formic acid) with a flow rate of 10 mL per minute and typicalgradients of 40 to 90% organic modifier ramped up over 30 to 40 minutes.Fractions containing the required product (identified by LCMS analysis)were pooled, the organic fraction removed by evaporation, and theremaining aqueous fraction lyophilised, to give the final product.

Example 1{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 1a: 3-(4-fluorophenylsulfanyl)thiophene-2-carbaldehyde

A mixture of sodium hydride (0.20 g) and n-butanol (10 mL) was treatedwith 4-fluorothiophenol (0.64 g), and the resulting mixture was added toa mixture of 3-bromothiophene-2-carbaldehyde (0.96 g),tetrakis(triphenylphosphine)palladium (0) (0.12 g) and n-butanol (5.0mL). The resulting mixture was stirred at 100° C. for 2 hours and thenat 120° C. for 4 hours. The mixture was cooled to room temperature,concentrated under reduced pressure and the residue partitioned betweenwater and ethyl acetate. The aqueous phase was extracted with ethylacetate, and the combined organic solution was dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel, eluting with a mixture ofcyclohexane and dichloromethane (2:1 to 0:1 by volume) to afford thetitle compound as a yellow solid (0.78 g).

¹H NMR (CDCl₃): δ 6.72 (d, J=5.1 Hz, 1H), 7.08 (t, J=8.6 Hz, 2H),7.42-7.48 (m, 2H), 7.62 (dd, J=1.0, 5.1 Hz, 1H), 10.11 (d, J=1.0 Hz,1H).

Preparation 1b: 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde

A solution of 3-(4-fluorophenylsulfanyl)thiophene-2-carbaldehyde (0.60g) in dichloromethane (6.0 mL) at 0° C. was treated dropwise with asolution of 3-chloroperoxybenzoic acid (1.3 g) in dichloromethane (12mL), and the resulting mixture was stirred at 0° C. for 15 minutes andthen at room temperature for 3 hours. The mixture was partitionedbetween saturated aqueous sodium hydrogen carbonate solution and ethylacetate. The aqueous phase was extracted with ethyl acetate, and thecombined organic solution was dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a mixture of cyclohexane anddichloromethane (1:3 to 0:1 by volume) to afford the title compound as awhite solid (0.36 g).

¹H NMR (CDCl₃): δ 7.22-7.26 (m, 2H), 7.46 (d, J=5.2 Hz, 1H), 7.71 (dd,J=1.2, 5.2 Hz, 1H), 7.96-8.01 (m, 2H), 10.63 (d, J=1.2 Hz, 1H).

Preparation 1c:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

A mixture of triethylsilane (0.79 g), trifluoroacetic acid (0.47 g) and1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with amixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.1g), 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde (0.15 g) and1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at−10° C. for 15 minutes and then at room temperature overnight. Themixture was diluted with dichloromethane, washed with saturated aqueoussodium hydrogen carbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue purified bycolumn chromatography on silica gel, eluting with a mixture ofcyclohexane and dichloromethane (1:1 to 0:1 by volume) to afford thetitle compound as a colourless gum (0.17 g).

¹H NMR (CDCl₃): δ 2.29 (s, 3H), 3.76 (s, 3H), 4.44 (s, 2H), 4.81 (s,2H), 6.66 (dd, J=2.5, 9.4 Hz, 1H), 6.87-6.91 (m, 1H), 7.05-7.10 (m, 2H),7.23 (t, J=8.6 Hz, 2H), 7.41 (d, J=5.4 Hz, 1H), 8.00 (dd, J=5.4, 8.9 Hz,2H).

Preparation 1d:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester (0.17 g), tetrahydrofuran (2.0 mL) and methanol (1.0mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.5 mL),and the resulting mixture was stirred at 40° C. overnight. The mixturewas acidified by the addition of 5.0 M aqueous hydrochloric acidsolution and concentrated to low bulk under reduced pressure. Theresulting precipitate was collected by filtration, washed with water anddried to afford the title compound as a cream solid (0.11 g).

¹H NMR (CDCl₃): δ 2.28 (s, 3H), 4.41 (s, 2H), 4.75 (s, 2H), 6.63 (dd,J=2.4, 9.5 Hz, 1H), 6.83 (td, J=2.5, 9.0 Hz, 1H), 7.05-7.12 (m, 2H),7.22 (t, J=8.4 Hz, 2H), 7.38 (s, 1H), 7.97 (dd, J=5.0, 8.5 Hz, 2H).

MS: ESI (+ve) (Method A): 462 (M+H)⁺, Retention time 11.0 min.

Example 2{5-fluoro-3-[4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

Preparation 2a: 4-(4-fluorophenylsulfanyl)benzaldehyde

A mixture of 4-fluorobenzenethiol (1.0 g), potassium carbonate (2.4 g)and N,N-dimethylformamide (25 mL) was treated with 4-bromobenzaldehyde(0.73 g), and the resulting mixture was stirred at room temperature for16 hours. The mixture was filtered and the filtrated concentrated underreduced pressure. The residue was purified by crystallisation from amixture of diethyl ether and cyclohexane to afford the title compound asa white solid (0.89 g).

¹H NMR (CDCl₃): δ 7.10-7.21 (m, 4H), 7.51-7.56 (m, 2H), 7.70-7.74 (m,2H), 9.92 (s, 1H).

Preparation 2b: 4-(4-fluorobenzenesulfonyl)benzaldehyde

The title compound was prepared by the method of Preparation 1b using4-(4-fluorophenylsulfanyl)benzaldehyde.

¹H NMR (CDCl₃): δ 7.19 (t, J=8.5 Hz, 2H), 7.95-8.01 (m, 4H), 8.08 (d,J=8.2 Hz, 2H), 10.06 (s, 1H).

Preparation 2c:{5-fluoro-3-[4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and4-(4-fluorobenzenesulfonyl)benzaldehyde.

¹H NMR (CDCl₃): δ 2.30 (s, 3H), 3.76 (s, 3H), 4.08 (s, 2H), 4.80 (s,2H), 6.84-6.96 (m, 2H), 7.05-7.19 (m, 3H), 7.29 (d, J=8.1 Hz, 2H), 7.79(d, J=8.2 Hz, 2H), 7.92 (dd, J=5.1, 8.9 Hz, 2H).

Preparation 2d:{5-fluoro-3-[4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticacid methyl ester (0.079 g) and tetrahydrofuran (1.0 mL) was treatedwith 5.0 M aqueous sodium hydroxide solution (1.5 mL), and the resultingmixture was stirred at 40° C. for 1 hour. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (1:3 to 9:1 by volume) to afford the title compound as a whitesolid (0.056 g).

¹H NMR (DMSO-d₆): δ 2.28 (s, 3H), 4.07 (s, 2H), 4.89 (s, 2H), 6.84 (td,J=2.5, 9.2 Hz, 1H), 7.12 (dd, J=2.5, 9.9 Hz, 1H), 7.32 (dd, J=4.4, 8.9Hz, 1H), 7.36-7.44 (m, 4H), 7.82 (d, J=8.4 Hz, 2H), 7.94-7.99 (m, 2H),12.91 (br s, 1H).

MS: ESI (+ve) (Method A): 456 (M+H)⁺, Retention time 11.2 min.

Example 3{5-fluoro-3-[3-fluoro-4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

Preparation 3a: 3-fluoro-4-(4-fluorophenylsulfanyl)benzaldehyde

A mixture of 4-fluorobenzenethiol (0.93 g), potassium carbonate (3.1 g)and N,N-dimethylformamide (25 mL) was treated with3,4-difluorobenzaldehyde (1.0 g), and the resulting mixture was stirredat room temperature for 16 hours. The mixture was partitioned betweenwater and ethyl acetate, and the organic phase was dried over magnesiumsulfate. The solvent was removed under reduced pressure to afford thetitle compound as a colourless gum (0.18 g).

¹H NMR (CDCl₃): δ 6.90 (t, J=7.6 Hz, 1H), 7.15 (t, J=8.6 Hz, 2H),7.45-7.58 (m, 4H), 9.88 (d, J=1.9 Hz, 1H).

Preparation 3b: 3-fluoro-4-(4-fluorobenzenesulfonyl)benzaldehyde

The title compound was prepared by the method of Preparation 1b using3-fluoro-4-(4-fluorophenylsulfanyl)benzaldehyde.

¹H NMR (CDCl₃): δ 7.23 (d, J=8.5 Hz, 2H), 7.62 (dd, J=1.4, 9.5 Hz, 1H),7.84 (dd, J=1.4, 8.0 Hz, 1H), 8.03-8.09 (m, 2H), 8.30 (t, J=7.3 Hz, 1H),10.04 (d, J=1.8 Hz, 1H).

Preparation 3c:{5-fluoro-3-[3-fluoro-4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and3-fluoro-4-(4-fluorobenzenesulfonyl)benzaldehyde.

¹H NMR (CDCl₃): δ 2.29 (s, 3H), 3.74 (s, 3H), 4.05 (s, 2H), 4.76-4.80(m, 2H), 6.82-6.94 (m, 3H), 7.05-7.08 (m, 1H), 7.10-7.20 (m, 3H),9.91-8.02 (m, 3H).

Preparation 3d:{5-fluoro-3-[3-fluoro-4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[3-fluoro-4-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticacid methyl ester (0.14 g) and tetrahydrofuran (1.0 mL) was treated with5.0 M aqueous sodium hydroxide solution (2.0 mL), and the resultingmixture was stirred at 40° C. for 1 hour. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (3.5:6.5 to 9:1, by volume) to afford the title compound as awhite solid (0.046 g).

¹H NMR (DMSO-d₆): δ 2.30 (s, 3H), 4.11 (s, 2H), 4.94 (s, 2H), 6.87 (td,J=2.5, 9.2 Hz, 1H), 7.16-7.23 (m, 2H), 7.30 (dd, J=1.5, 8.2 Hz, 1H),7.36 (dd, J=4.4, 8.9 Hz, 1H), 7.42-7.49 (m, 2H), 7.90-8.02 (m, 3H),13.10 (br s, 1H).

MS: ESI (+ve) (Method A): 473 (M+H)⁺, Retention time 11.4 min.

Example 4{3-[2-(4-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

Preparation 4a: 2-(4-chlorobenzenesulfonyl)pyridine-3-carbaldehyde

The title compound was prepared by the method of Preparation 1b using2-(4-chlorophenylsulfanyl)pyridine-3-carbaldehyde.

¹H NMR (CDCl₃): δ 7.55-7.64 (m, 3H), 7.98-8.03 (m, 2H), 8.40 (dd, J=1.8,7.9 Hz, 1H), 8.69 (dd, J=1.7, 4.7 Hz, 1H), 11.13 (d, J=0.8 Hz, 1H).

Preparation 4b:{3-[2-(4-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and2-(4-chlorobenzenesulfonyl)pyridine-3-carbaldehyde.

¹H NMR (CDCl₃): δ 2.31 (s, 3H), 3.77 (s, 3H), 4.64 (s, 2H), 4.83 (s,2H), 6.80-6.94 (m, 2H), 7.11 (dd, J=4.2, 8.8 Hz, 1H), 7.22 (dd, J=4.6,7.9 Hz, 1H), 7.36-7.40 (m, 1H), 7.54-7.59 (m, 2H), 7.98-8.03 (m, 2H),8.30 (dd, J=1.6, 4.6 Hz, 1H).

Preparation 4c:{3-[2-(4-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

A mixture of{3-[2-(4-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticacid methyl ester (0.19 g) and tetrahydrofuran (1.5 mL) was treated with5.0 M aqueous sodium hydroxide solution (2.0 mL), and the resultingmixture was stirred at 40° C. for 3 hours. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (3.5:6.5 to 9:1 by volume) to afford the title compound as awhite solid (0.039 g).

¹H NMR (DMSO-d₆): δ 2.30 (s, 3H), 4.57 (s, 2H), 4.98 (s, 2H), 6.85-6.92(m, 2H), 7.37-7.50 (m, 3H), 7.74-7.79 (m, 2H), 8.00-8.04 (m, 2H), 8.37(dd, J=1.7, 4.4 Hz, 1H), 13.00 (br s, 1H).

MS: ESI (+ve) (Method A): 473 (M+H)⁺, Retention time 11.1 min.

Example 5{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-4-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 5a: 3-(4-fluorobenzenesulfonyl)pyridine-4-carbaldehyde

A solution of 3-fluoroisonicotinaldehyde (0.25 mL) in dimethyl sulfoxide(2.0 mL) was treated with a solution of 4-fluorobenzene sulfinic acidsodium salt (0.5 g) in dimethyl sulfoxide (3.0 mL), and the resultingmixture was stirred at 100° C. for 3 days. The mixture was cooled toroom temperature, partitioned between water and ethyl acetate (20 mL),and the aqueous phase extracted with ethyl acetate. The combined organicsolution was dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to4:1 by volume) to afford the title compound as a white solid (0.38 g).

¹H NMR (CDCl₃): δ 7.24-7.29 (m, 2H), 7.76 (dd, J=0.7, 4.9 Hz, 1H),7.95-8.01 (m, 2H), 9.02 (d, J=4.9 Hz, 1H), 9.30 (s, 1H), 10.88 (d, J=0.7Hz, 1H).

Preparation 5b:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-4-ylmethyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and3-(4-fluorobenzenesulfonyl)pyridine-4-carbaldehyde.

¹H NMR (CDCl₃): δ 2.16 (s, 3H), 3.76 (s, 3H), 4.25 (s, 2H), 4.79 (s,2H), 6.34 (dd, J=2.5, 9.3 Hz, 1H), 6.82-6.90 (m, 2H), 7.08 (dd, J=4.1,8.9 Hz, 1H), 7.28 (dd, J=2.0, 8.3 Hz, 2H), 8.02 (dd, J=5.0, 8.9 Hz, 2H),8.55 (d, J=5.1 Hz, 1H), 9.32 (s, 1H).

Preparation 5c:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-4-ylmethyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-4-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester (0.21 g) and tetrahydrofuran (1.0 mL) was treated with5.0 M aqueous sodium hydroxide solution (3.0 mL), and the resultingmixture was stirred at 40° C. for 3 hours. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution andconcentrated to low bulk under reduced pressure. The resultingprecipitate was collected by filtration, washed with water and dried toafford the title compound as a white solid (0.094 g).

¹H NMR (DMSO-d₆): δ 2.11 (s, 3H), 4.21 (s, 2H), 4.97 (s, 2H), 6.25 (dd,J=2.5, 9.8 Hz, 1H), 6.84 (td, J=2.5, 9.2 Hz, 1H), 6.90 (d, J=5.2 Hz,1H), 7.37 (dd, J=4.4, 8.9 Hz, 1H), 7.47-7.56 (m, 2H), 8.13-8.19 (m, 2H),8.66 (d, J=5.1 Hz, 1H), 9.27 (s, 1H), 13.05 (br s, 1H).

MS: ESI (+ve) (Method A): 457 (M+H)⁺, Retention time 10.1 min.

Example 6(5-fluoro-3-{2-[(4-fluorophenyl)methylsulfamoyl]benzyl}-2-methylindol-1-yl)aceticAcid

Preparation 6a: 2-[(4-fluorophenyl)methylsulfamoyl]benzoic Acid MethylEster

A solution of 4-fluoro-N-methylaniline (0.53 g), triethylamine (0.65 g)and dichloromethane (2.0 mL) was treated with 2-chlorosulfonylbenzoicacid methyl ester (1.0 g), and the resulting mixture was stirred at roomtemperature for 24 hours. The mixture was partitioned between water anddichloromethane, and the organic phase was washed with saturated aqueoussodium chloride solution and dried over sodium sulfate. The solvent wasremoved under reduced pressure and the residue was purified by columnchromatography on SCX-2, eluting with methanol and then 2.0 M ammonia inmethanol to afford the title compound as a pale yellow solid (1.2 g).

¹H NMR (CDCl₃): δ 3.26 (s, 3H), 3.86 (s, 3H), 6.96-7.04 (m, 2H),7.11-7.18 (m, 2H), 7.36-7.49 (m, 3H), 7.58 (ddd, J=1.7, 6.8, 7.7 Hz,1H).

Preparation 6b:N-(4-fluorophenyl)-2-hydroxymethyl-N-methylbenzenesulfonamide

A solution of 2-[(4-fluorophenyl)methylsulfamoyl]benzoic acid methylester (0.80 g) in tetrahydrofuran at −20° C. was treated dropwise with1.0 M lithium aluminium hydride solution in tetrahydrofuran (2.5 mL),and the resulting mixture was stirred at −20° C. for 3 hours. Themixture was treated with 1.0 M aqueous hydrochloric acid solution andRochelle's salt, and the resulting mixture was stirred at roomtemperature for 1 hour. The mixture was extracted with ethyl acetate andthe combined organic extract was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a mixture of cyclohexane andethyl acetate (1:0 to 6:4 by volume) to afford the title compound ascolourless oil (0.35 g).

¹H NMR (CDCl₃): δ 3.21 (s, 3H), 4.38 (d, J=6.6 Hz, 2H), 6.95-7.12 (m,4H), 7.44 (ddd, J=1.9, 7.0, 7.9 Hz, 1H), 7.53-7.63 (m, 2H), 7.79 (dd,J=1.3, 7.9 Hz, 1H).

Preparation 6c: N-(4-fluorophenyl)-2-formyl-N-methylbenzenesulfonamide

A solution ofN-(4-fluorophenyl)-2-hydroxymethyl-N-methylbenzenesulfonamide (0.35 g)in chloroform (20 mL) was treated with manganese dioxide (1.2 g), andthe resulting mixture was stirred at 60° C. for 16 hours. The mixturewas filtered through Celite and the filtrate concentrated under reducedpressure to afford the title compound as colourless oil (0.23 g).

¹H NMR (CDCl₃): δ 3.18 (s, 3H), 6.96-7.08 (m, 4H), 7.68-7.75 (m, 2H),7.88-7.94 (m, 1H), 8.00-8.06 (m, 1H), 9.99 (s, 1H).

Preparation 6d:(5-fluoro-3-{2-[(4-fluorophenyl)methylsulfamoyl]benzyl}-2-methylindol-1-yl)aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester andN-(4-fluorophenyl)-2-formyl-N-methylbenzenesulfonamide.

¹H NMR (CDCl₃): δ 2.20 (s, 3H), 3.29 (s, 3H), 3.75 (s, 3H), 4.17 (s,2H), 4.80 (s, 2H), 6.78-6.92 (m, 2H), 6.93-7.11 (m, 4H), 7.21-7.25 (m,1H), 7.25-7.35 (m, 3H), 7.89 (dd, J=1.8, 7.6 Hz, 1H).

Preparation 6e:(5-fluoro-3-{2-[(4-fluorophenyl)methylsulfamoyl]benzyl}-2-methylindol-1-yl)aceticAcid

A mixture of(5-fluoro-3-{2-[(4-fluorophenyl)methylsulfamoyl]benzyl}-2-methylindol-1-yl)aceticacid methyl ester (0.22 g) and tetrahydrofuran (1.0 mL) was treated with5.0 M aqueous sodium hydroxide solution (3.0 mL), and the resultingmixture was stirred at 40° C. for 3 hours. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (3.5:6.5 to 9:1 by volume) to afford the title compound as awhite solid (0.10 g).

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 3.25 (s, 3H), 4.03 (s, 2H), 4.97 (s,2H), 6.76-6.93 (m, 3H), 7.20-7.28 (m, 2H), 7.31-7.40 (m, 4H), 7.45 (td,J=1.5, 7.5 Hz, 1H), 7.82 (dd, J=1.4, 7.9 Hz, 1H), 13.02 (br s, 1H).

MS: ESI (+ve) (Method A): 485 (M+H)⁺, Retention time 11.7 min.

Example 7{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 7a: 3-(4-fluorobenzenesulfonyl)pyridine-2-carbaldehyde

A mixture of 3-fluoropyridine-2-carbaldehyde (0.70 g),4-fluorobenzenesulfinic acid sodium salt (1.1 g) and dimethyl sulfoxide(7.0 mL) was stirred at 100° C. for 18 hours. The mixture was cooled toroom temperature, diluted with water (20 mL), and the resultingprecipitate was removed by filtration. The filtrate was extracted withethyl acetate, and the combined organic extract was washed withsaturated aqueous sodium chloride solution and dried over magnesiumsulfate. The solvent was removed under reduced pressure to afford thetitle compound as a pale yellow oil (0.67 g).

¹H NMR (CDCl₃): δ 7.23 (m, 2H), 7.22 (dd, J=4.7, 8.0 Hz, 1H), 8.03 (m,2H), 8.63 (ddd, J=0.3, 1.5, 8.0 Hz, 1H), 8.97 (dd, J=1.5, 4.7 Hz, 1H),10.36 (s, 1H).

Preparation 7b:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-2-ylmethyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and3-(4-fluorobenzenesulfonyl)pyridine-2-carbaldehyde.

¹H NMR (CDCl₃): δ 2.26 (s, 3H), 3.75 (s, 3H), 4.45 (s, 2H), 4.74 (s,2H), 6.32 (dd, J=2.5, 9.8 Hz, 1H), 6.78 (dt, J=2.5, 9.0 Hz, 1H), 6.98(m, 1H), 7.12 (m, 2H), 7.37 (m, 1H), 7.83 (m, 2H), 8.51 (dd, J=1.7, 8.0Hz, 1H), 8.68 (dd, J=1.7, 4.8 Hz, 1H).

MS: ESI (+ve) (Method B): 471 (M+H)⁺, Retention time 3.7 min.

Preparation 7c:{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

A solution of{5-fluoro-3-[3-(4-fluorobenzenesulfonyl)pyridin-2-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester (0.18 g) in tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.45 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a white solid(0.13 g).

¹H NMR (DMSO-d₆): δ 2.15 (s, 3H), 4.36 (s, 2H), 4.88 (s, 2H), 6.21 (dd,J=2.5, 10.1 Hz, 1H), 6.75 (dt, J=2.5, 9.1 Hz, 1H), 7.25 (m, 1H), 7.40(t, J=8.8 Hz, 2H), 7.58 (m, 1H), 7.96 (m, 2H), 8.53 (dd, J=1.6, 8.1 Hz,1H), 8.70 (dd, J=1.6, 4.7 Hz, 1H), 13.05 (br s, 1H).

MS: ESI (+ve) (Method A): 457 (M+H)⁺, Retention time 10.1 min.

Example 8{5-fluoro-3-[3-fluoro-2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

Preparation 8a: 3-fluoro-2-(4-fluorophenylsulfanyl)benzaldehyde

The title compound was prepared by the method of Preparation 3a using2,3-difluorobenzaldehyde.

¹H NMR (CDCl₃): δ 6.92-7.01 (m, 2H), 7.20-7.27 (m, 2H), 7.38 (td, J=1.5,8.3 Hz, 1H), 7.48-7.56 (m, 1H), 7.81 (ddd, J=0.7, 1.5, 7.7 Hz, 1H),10.70 (d, J=0.8 Hz, 1H).

Preparation 8b: 3-fluoro-2-(4-fluorobenzenesulfonyl)benzaldehyde

The title compound was prepared by the method of Preparation 1b using3-fluoro-2-(4-fluorophenylsulfanyl)benzaldehyde.

¹H NMR (CDCl₃): δ 7.20-7.35 (m, 3H), 7.63-7.73 (m, 2H), 8.07 (ddd,J=1.6, 5.0, 8.9 Hz, 2H), 11.00 (d, J=0.7 Hz, 1H).

Preparation 8c:{5-fluoro-3-[3-fluoro-2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and2-benzenesulfonyl-3-fluorobenzaldehyde.

¹H NMR (CDCl₃): δ 2.30 (s, 3H), 3.77 (s, 3H), 4.68 (s, 2H), 4.84 (s,2H), 6.66 (dd, J=2.5, 9.5 Hz, 1H), 6.82-6.98 (m, 3H), 7.10 (dd, J=4.2,8.7 Hz, 1H), 7.18 (m, 2H), 7.31 (td, J=5.5, 7.9 Hz, 1H), 7.98 (ddd,J=1.4, 5.1, 8.8 Hz, 2H).

Preparation 8d:{5-fluoro-3-[3-fluoro-2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 2d using{5-fluoro-3-[3-fluoro-2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.23 (s, 3H), 4.60 (s, 2H), 5.00 (s, 2H), 6.70 (dd,J=2.4, 9.6 Hz, 1H), 6.84-6.89 (m, 2H), 7.24 (dd, J=8.3, 10.9 Hz, 1H),7.39 (dd, J=4.5, 8.9 Hz, 1H), 7.46 (m, 2H), 7.53 (ddd, J=1.4, 5.1, 8.8Hz, 1H), 8.04 (dd, J=5.1, 8.3 Hz, 2H), 13.06 (br s, 1H).

MS: ESI (+ve) (Method A): 474 (M+H)⁺, Retention time 11.4 min.

Example 9[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 9a: 3-phenylsulfanylthiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 1a usingbenzenethiol and 3-bromothiophene-2-carbaldehyde.

¹H NMR (CDCl₃): δ 6.81 (d, J=5.07 Hz, 1H), 7.32-7.38 (m, 3H), 7.40-7.44(m, 2H), 7.63 (dt, J=1.0, 5.0 Hz, 1H), 10.13 (d, J=1.2 Hz, 1H).

Preparation 9b: 3-benzenesulfonylthiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 1b using3-phenylsulfanylthiophene-2-carbaldehyde

¹H NMR (CDCl₃): δ 7.49 (d, J=5.2 Hz, 1H), 7.54-7.61 (m, 2H), 7.62-7.68(m, 1H), 7.70 (dd, J=1.2, 5.2 Hz, 1H), 7.95-8.00 (m, 2H), 10.64 (d,J=1.2 Hz, 1H).

MS: ESI (+ve) (Method B): 253 (M+H)⁺, Retention time 3.2 min.

Preparation 9c:[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and3-benzenesulfonylthiophene-2-carbaldehyde.

¹H NMR (DMSO-d₆): δ 2.20 (s, 3H), 3.67 (s, 3H), 4.45 (s, 2H), 5.12 (s,2H), 6.69 (dd, J=2.5, 9.8 Hz, 1H), 6.87 (dt, J=2.5, 9.2 Hz, 1H),7.35-7.41 (m, 2H), 7.44 (d, J=5.4 Hz, 1H), 7.65-7.79 (m, 3H), 8.03-8.07(m, 2H).

MS: ESI (+ve) (Method B): 458 (M+H)⁺, Retention time 3.9 min.

Preparation 9d:[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A solution of[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.19 g) in tetrahydrofuran (10 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.8 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a white solid(0.17 g).

¹H NMR (DMSO-d₆): δ 2.14 (s, 3H), 4.38 (s, 2H), 4.88 (s, 2H), 6.61 (dd,J=2.5, 9.8 Hz, 1H), 6.80 (dt, J=2.5, 9.2 Hz, 1H), 7.30 (dd, J=4.3, 8.8Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 7.37 (d, J=5.5 Hz, 1H), 7.60-7.64 (m,2H), 7.67-7.72 (m, 1H), 7.97-7.99 (m, 2H), 13.02 (br s, 1H).

MS: ESI (+ve) (Method A): 444 (M+H)⁺, Retention time 10.7 min.

Example 10[3-(2-benzenesulfonylpyridin-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 10a: 2-benzenesulfonylpyridine-3-carbaldehyde

The title compound was prepared by the method of Preparation 1b using2-phenylsulfanylpyridine-3-carbaldehyde

¹H NMR (DMSO-d₆): δ 7.62-7.73 (m, 2H), 7.78-7.88 (m, 2H), 8.03-8.08 (m,2H), 8.33 (dd, J=1.7, 7.7 Hz, 1H), 8.82 (dd, J=1.7, 4.7 Hz, 1H), 10.90(d, J=0.7 Hz, 1H).

Preparation 10b:[3-(2-benzenesulfonylpyridin-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-benzenesulfonylpyridine-3-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.28 (s, 3H), 3.77 (s, 3H), 4.60 (s, 2H), 4.82 (s,2H), 6.71 (dd, J=2.4, 9.4 Hz, 1H), 6.88 (dt, J=2.4, 9.0 Hz, 1H), 7.10(dd, J=4.1, 8.8 Hz, 1H), 7.21 (dd, J=4.5, 7.9 Hz, 1H), 7.33-7.37 (m,1H), 7.56-7.63 (m, 2H), 7.66-7.72 (m, 1H), 8.07-8.11 (m, 2H), 8.36 (m1H).

MS: ESI (+ve) (Method B): 453 (M+H)⁺, Retention time 3.8 min.

Preparation 10c:[3-(2-benzenesulfonylpyridin-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of[3-(2-benzenesulfonylpyridin-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.16 g) and tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.5 mL), and the resultingmixture was stirred at room temperature for 30 minutes. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(5:95 to 98:2 by volume) to afford the title compound as a white solid(0.11 g).

¹H NMR (DMSO-d₆): δ 2.26 (s, 3H), 4.55 (s, 2H), 4.94 (s, 2H), 6.86-6.89(m, 2H), 7.35-7.42 (m, 2H), 7.45 (dd, J=4.4, 8.9 Hz, 1H), 7.68-7.72 (m,2H), 7.79 (tt, J=1.2, 7.5 Hz, 1H), 8.00-8.02 (m, 2H), 8.36 (dd, J=1.5,4.4 Hz, 1H), 13.2 (br s, 1H).

MS: ESI (+ve) (Method A): 439 (M+H)⁺, Retention time 10.1 min.

Example 11[3-(3-benzenesulfonylpyridin-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 11a: 3-benzenesulfonylpyridine-2-carbaldehyde

The title compound was prepared by the method of Preparation 5a using3-fluoropyridine-2-carbaldehyde and benzene sulfinic acid sodium salt.

¹H NMR (DMSO-d₆): δ 7.62-7.73 (m, 2H), 7.72-7.79 (m, 1H), 7.95 (dd,J=4.7, 8.1 Hz, 1H), 8.01-8.06 (m, 2H), 8.67 (dd, J=1.4, 8.1 Hz, 1H),9.05 (dd, J=1.4, 4.7 Hz, 1H), 10.36 (s, 1H).

Preparation 11b:[3-(3-benzenesulfonylpyridin-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using3-benzenesulfonylpyridine-2-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.22 (s, 3H), 3.73 (s, 3H), 4.41 (s, 2H), 4.71 (s,2H), 6.31 (dd, J=2.5, 9.7 Hz, 1H), 6.76 (dt, J=2.5, 9.2 Hz, 1H), 6.97(dd, J=4.2, 8.8 Hz, 1H), 7.31-7.38 (m, 1H), 7.46-7.53 (m, 2H), 7.56-7.63(m, 1H), 7.84-7.89 (m, 2H), 8.52 (dd, J=1.7, 8.0 Hz, 1H), 8.63 (dd,J=1.7, 4.7 Hz, 1H).

MS: ESI (+ve) (Method B): 453 (M+H)⁺, Retention time 3.7 min.

Preparation 11c:[3-(3-benzenesulfonylpyridin-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of[3-(3-benzenesulfonylpyridin-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.19 g) and tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.62 mL), and the resultingmixture was stirred at room temperature for 30 minutes. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a white solid(0.15 g).

¹H NMR (DMSO-d₆): δ 2.10 (s, 3H), 4.33 (s, 2H), 4.88 (s, 2H), 6.33 (dd,J=2.5, 10.1 Hz, 1H), 6.75 (dt, J=2.5, 9.2 Hz, 1H), 7.24 (dd, J=4.4, 8.9Hz, 1H), 7.56 (dd, J=4.7, 8.0 Hz, 1H), 7.60-7.64 (m, 2H), 7.71-7.73 (m,1H), 7.91-7.94 (m, 2H), 8.53 (dd, J=1.7, 8.0 Hz, 1H), 8.67 (dd, J=1.7,4.7 Hz, 1H) 13.01 (br s, 1H).

MS: ESI (+ve) (Method A): 439 (M+H)⁺, Retention time 9.9 min.

Example 12{5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}aceticAcid

Preparation 12a: 2-(thiophen-2-ylsulfanyl)benzaldehyde

A mixture of thiophene-2-thiol (1.5 mL), potassium carbonate (8.0 g) andN,N-dimethylformamide was treated dropwise with 2-fluorobenzaldehyde(1.7 mL), and the resulting mixture was stirred at room temperature for42 hours. The mixture was treated with ice/water, extracted with ethylacetate and the combined organic extract was dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuepurified by column chromatography on silica gel, eluting with a mixtureof cyclohexane and ethyl acetate (1:0 to 9:1 by volume), followed bydistillation at 50° C./11 mbar to afford the title compound as a red oil(1.9 g).

¹H NMR (CDCl₃): δ 6.97 (d, J=8.1 Hz, 1H), 7.16 (dd, J=3.6, 5.4 Hz, 1H),7.29 (ddd, J=1.1, 7.5, 7.5 Hz, 1H), 7.34 (dd, J=1.3, 3.6 Hz, 1H), 7.40(ddd, J=1.7, 7.3, 8.1 Hz, 1H), 7.59 (dd, J=1.2, 5.3 Hz, 1H), 7.82 (dd,J=1.6, 7.5 Hz, 1H), 10.27 (s, 1H).

MS: ESI (+ve) (Method B): Retention time 3.8 min.

Preparation 12b: 2-(thiophene-2-sulfonyl)benzaldehyde

A mixture of 2-(thiophen-2-ylsulfanyl)benzaldehyde (0.30 g) anddichloromethane (13 mL) was treated portion wise with3-chloroperoxybenzoic acid (67% in water, 0.70 g), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasdiluted with dichloromethane (150 mL), washed with saturated aqueoussodium bicarbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford the title compoundas a yellow solid (0.29 g).

¹H NMR (CDCl₃): δ 7.13 (dd, J=4.9, 3.9 Hz, 1H), 7.71-7.80 (m, 4H), 8.05(m, 1H), 8.18 (m, 1H), 11.01 (d, J=0.6 Hz, 1H).

MS: ESI (+ve) (Method B): Retention time 3.3 min.

Preparation 12c:{5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-(thiophene-2-sulfonyl)benzaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.21 (s, 3H), 3.76 (s, 3H), 4.42 (s, 2H), 4.81 (s,2H), 6.43 (dd, J=2.4, 9.5 Hz, 1H), 6.85 (dd, J=2.5, 9.0 Hz, 1H), 6.96(m, 1H), 7.07 (dd, J=4.1, 8.9 Hz, 1H), 7.13 (dd, J=3.8, 5.0 Hz, 1H),7.37 (m, 2H), 7.71 (dd, J=1.3, 5.1 Hz, 1H), 7.78 (dd, J=1.3, 3.8 Hz,1H), 8.24 (m, 1H).

MS: ESI (+ve) (Method B): 458 (M+H)⁺, Retention time 4.0 min.

Preparation 12d:{5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}aceticAcid

A mixture of{5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}aceticacid methyl ester (0.21 g) and tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (1.2 mL), and the resultingmixture was stirred at room temperature for 2 hours. The mixture wasdiluted with water (25 mL), concentrated to low bulk under reducedpressure and the pH adjusted to 4 by the addition of 0.1 M aqueoushydrochloric acid solution. The mixture was extracted with ethyl acetateand the combined organic extract was washed with saturated aqueoussodium chloride solution and dried over magnesium sulfate. The solventwas removed under reduced pressure and the residue purified by columnchromatography on silica gel, eluting with a mixture of dichloromethaneand ethyl acetate containing 0.1% formic acid (1:0 to 0:1 by volume),followed by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (3:7 to 9:1 by volume) to afford the titlecompound as a white solid (0.14 g).

¹H NMR (DMSO-d₆): δ 2.10 (s, 3H), 4.30 (s, 2H), 4.92 (s, 2H), 6.39 (dd,J=2.6, 9.7 Hz, 1H), 6.79 (ddd, J=2.3, 9.3, 9.3 Hz, 1H), 6.88 (dd, J=2.4,6.9 Hz, 1H), 7.23 (dd, J=3.7, 4.8 Hz, 1H), 7.32 (dd, J=4.4, 8.8 Hz, 1H),7.41-7.49 (m, 2H), 7.89 (dd, J=1.3, 4.0 Hz, 1H), 8.08-8.12 (m, 2H),13.00 (s, 1H).

MS: ESI (+ve) (Method A): 444 (M+H)⁺, Retention time 10.9 min.

Example 13{5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

Preparation 13a: 3-(thiophen-2-ylsulfanyl)thiophene-2-carbaldehyde

A mixture of 3-chlorothiophene-2-carbaldehyde (1.0 g), potassiumcarbonate (2.8 g) and N,N-dimethylformamide (6.8 mL) was treateddropwise with thiophene-2-thiol (0.87 g), and the resulting mixture wasstirred at room temperature for 3 hours. The mixture was poured ontowater (150 mL) and extracted with diethyl ether. The combined organicextract was washed with saturated aqueous sodium hydrogen carbonatesolution and saturated aqueous sodium chloride solution, and then driedover magnesium sulfate. The solvent was removed under reduced pressureto afford the title compound as a red oil (1.5 g).

¹H NMR (CDCl₃): δ 6.72 (d, J=5.3 Hz, 1H), 7.09 (dd, J=3.5, 5.6 Hz, 1H),7.34 (dd, J=1.3, 3.5 Hz, 1H), 7.52 (dd, J=1.3, 5.3 Hz, 1H), 7.58 (dd,J=0.9, 5.2 Hz, 1H), 10.09 (d, J=1.0 Hz, 1H).

MS: ESI (+ve) (Method B): Retention time 3.6 min.

Preparation 13b: 3-(thiophene-2-sulfonyl)thiophene-2-carbaldehyde

A mixture of 3-(thiophen-2-ylsulfanyl)thiophene-2-carbaldehyde (1.5 g)and dichloromethane (68 mL) was treated with 3-chloroperoxybenzoic acid(70% in water, 4.6 g), and the resulting mixture was stirred at roomtemperature for 18 hours. The mixture was diluted with saturated aqueoussodium thiosulfate solution (50 mL), extracted with diethyl ether andthe combined organic extract was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution, andthen dried over magnesium sulfate. The solvent was removed under reducedpressure to afford the title compound as a brown solid (1.2 g).

¹H NMR (CDCl₃): δ 7.15 (dd, J=3.8, 5.1 Hz, 1H), 7.53 (d, J=5.3 Hz, 1H),7.70 (dd, J=1.3, 5.1 Hz, 1H), 7.75 (dd, J=1.3, 4.8 Hz, 1H), 7.77 (dd,J=1.4, 3.8 Hz, 1H), 10.66 (d, J=1.3 Hz).

MS: ESI (+ve) (Method B): Retention time 3.3 min.

Preparation 13c:{5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.14g), 3-(thiophene-2-sulfonyl)thiophene-2-carbaldehyde (0.12 g) anddichloroethane (5.0 mL) at 0° C. was treated dropwise with a mixture oftriethylsilane (1.4 mL), trifluoroacetic acid (0.35 mL) anddichloroethane (2.0 mL), and the resulting mixture was stirred at roomtemperature for 1 hour. The mixture was cooled to 0° C., diluted withsaturated aqueous sodium hydrogen carbonate solution and the phasesseparated. The aqueous phase was extracted with dichloromethane and thecombined organic solution was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a mixture of cyclohexane andethyl acetate (1:0 to 1:1 by volume), to afford the title compound as ayellow solid (0.17 g).

¹H NMR (DMSO-d₆): δ 2.23 (s, 3H), 3.68 (s, 3H), 4.50 (s, 2H), 5.12 (s,2H), 6.83 (dd, J=2.5, 9.7 Hz, 1H), 6.89 (ddd, J=2.5, 9.2, 9.2 Hz, 1H),7.28 (dd, J=3.8, 4.9 Hz, 1H), 7.36 (d, J=5.6 Hz, 1H), 7.39 (dd, J=4.3,9.0 Hz, 1H), 7.44 (d, J=5.6 Hz, 1H), 7.95 (dd, J=1.5, 3.8 Hz, 1H), 8.13(dd, J=1.5, 4.8 Hz, 1H).

MS: ESI (+ve) (Method B): 464 (M−1-H)⁺, Retention time 3.9 min.

Preparation 13d:{5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

A mixture of{5-fluoro-2-methyl-3-[3-(thiophene-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester (0.17 g), tetrahydrofuran (0.35 mL) and water (0.35mL) was treated with lithium hydroxide (0.088 g), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wascooled to 0° C., pH adjusted to 5 by the addition of 1.0 M aqueoushydrochloric acid solution and extracted with ethyl acetate. Thecombined organic extract was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by preparative reverse-phaseHPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 byvolume) to afford the title compound as a white solid (0.089 g).

¹H NMR (DMSO-d₆): δ 2.19 (s, 3H), 4.46 (s, 2H), 4.93 (s, 2H), 6.77 (dd,J=2.6, 9.8 Hz, 1H), 6.83 (ddd, J=2.5, 9.2, 9.2 Hz, 1H), 7.24 (dd, J=4.0,4.8 Hz), 7.31 (d, J=5.5 Hz), 7.34 (dd, J=4.4, 4.4 Hz), 7.39 (d, J=5.4Hz, 1H), 7.91 (dd, J=1.3, 3.5 Hz, 1H), 8.09 (dd, J=1.3, 4.9 Hz, 1H),12.96 (br s, 1H).

MS: ESI (+ve) (Method A): 450 (M+H)⁺, Retention time 10.7 min.

Example 14[3-(2-benzenesulfonyl-4-chlorobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 14a: 2-benzenesulfonyl-4-chlorobenzaldehyde

The title compound was prepared by the method of Preparation 5a using4-chloro-2-fluorobenzaldehyde and benzene sulfinic acid sodium salt.

¹H NMR (CDCl₃): δ 7.54-7.61 (m, 2H), 7.62-7.71 (m, 2H), 7.89-7.93 (m,2H), 7.98 (d, J=8.3 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 10.79 (d, J=0.8 Hz,1H).

Preparation 14b:[3-(2-benzenesulfonyl-4-chlorobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-benzenesulfonyl-4-chlorobenzaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (DMSO-d₆): δ 2.04 (s, 3H), 3.67 (s, 3H), 4.11 (s, 2H), 5.08 (s,2H), 6.18 (dd, J=2.5, 9.8 Hz, 1H), 6.79-6.88 (m, 2H), 7.35 (dd, J=4.4,8.9 Hz, 1H), 7.59-7.72 (m, 3H), 7.78 (d, J=7.3 Hz, 1H), 8.01-8.06 (m,2H), 8.21 (d, J=2.3 Hz, 1H).

MS: ESI (+ve) (Method B): 486 (M+H)⁺, Retention time 4.2 min.

Preparation 14c:[3-(2-benzenesulfonyl-4-chlorobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A solution of[3-(2-benzenesulfonyl-4-chlorobenzyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.16 g) in tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.5 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a white solid(0.15 g).

¹H NMR (DMSO-d₆): δ 2.04 (s, 3H), 4.10 (s, 2H), 4.92 (s, 2H), 6.18 (dd,J=2.5, 9.7 Hz, 1H), 6.81 (dt, J=2.5, 9.2 Hz, 1H), 6.87 (d, J=8.4 Hz,1H), 7.34 (dd, J=4.4, 8.9 Hz, 1H), 7.61 (dd, J=2.4, 8.4 Hz, 1H),7.67-7.71 (m, 2H), 7.77-7.80 (m, 1H), 8.02-8.05 (m, 2H), 8.20 (d, J=2.4Hz, 1H) 13.04 (br s, 1H).

MS: ESI (+ve) (Method A): 472 (M+H)⁺, Retention time 12.0 min.

Example 15[3-(2-benzenesulfonyl-4-cyanobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 15a: 3-benzenesulfonyl-4-formylbenzonitrile

The title compound was prepared by the method of Preparation 5a using3-fluoro-2-phenylsulfanylbenzaldehyde.

¹H NMR (CDCl₃): δ 7.74-7.58 (m, 3H), 7.91-8.01 (m, 3H), 8.11 (d, J=8.0Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 10.89 (d, J=0.8 Hz, 1H).

Preparation 15b:[3-(2-benzenesulfonyl-4-cyanobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using3-benzenesulfonyl-4-formylbenzonitrile and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (DMSO-d₆): δ 2.02 (s, 3H), 3.65 (s, 3H), 4.19 (s, 2H), 5.07 (s,2H), 6.17 (dd, J=2.6, 9.7 Hz, 1H), 6.83 (dt, J=2.4, 9.0 Hz, 1H), 7.01(d, J=8.1 Hz, 1H), 7.36 (dd, J=4.4, 9.0 Hz, 1H), 7.70 (t, J=7.8 Hz, 2H),7.79 (t, J=7.8 Hz, 1H), 8.00 (dd, J=1.9, 8.1 Hz, 1H), 8.07 (d, J=7.1 Hz,2H), 8.61 (d, J=1.8 Hz, 1H).

Preparation 15c:[3-(2-benzenesulfonyl-4-cyanobenzyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A solution of[3-(2-benzenesulfonyl-4-cyanobenzyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.11 g) in tetrahydrofuran (0.30 mL) was treated with1.0 M aqueous lithium hydroxide solution (2.0 mL), and the resultingmixture was stirred at room temperature for 2 hours. The mixture wasacidified by the addition of 1.0 M aqueous hydrochloric acid solutionand concentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (2:3 to 19:1 by volume) to afford the title compound as awhite solid (0.058 g).

¹H NMR (DMSO-d₆): δ 2.04 (s, 3H), 4.21 (s, 2H), 4.93 (s, 2H), 6.16 (dd,J=2.5, 9.7 Hz, 1H), 6.82 (dt, J=2.5, 9.1 Hz, 1H), 7.03 (d, J=8.2 Hz,1H), 7.35 (dd, J=4.4, 8.7 Hz, 1H), 7.69 (t, J=7.4 Hz, 2H), 7.80 (m, 1H),7.98 (dd, J=1.8, 8.2 Hz, 1H), 8.08 (dd, J=1.5, 7.9 Hz, 2H), 8.62 (d,J=1.8 Hz, 1H), 13.03 (br s, 1H).

MS: ESI (+ve) (Method A): 463 (M+H)⁺, Retention time 11.0 min.

Example 16{5-fluoro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

Preparation 16a: 3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 5a using2-formyl-3-chlorothiophene and pyridine-2-sulfinic acid sodium salt.

¹H NMR (CDCl₃): δ 7.52 (ddd, J=1.2, 4.6, 7.5 Hz, 1H), 7.58 (d, J=5.2 Hz,1H), 7.69 (dd, J=1.2, 5.2 Hz, 1H), 7.98 (td, J=1.7, 7.8 Hz, 1H), 8.24(dt, J=1.0, 7.9 Hz, 1H), 8.70 (ddd, J=0.9, 1.7, 4.7 Hz, 1H), 10.70 (d,J=1.2 Hz, 1H).

Preparation 16b:{5-fluoro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.34 (s, 3H), 3.76 (s, 3H), 4.71 (s, 2H), 4.81 (s,2H), 6.82-6.95 (m, 2H), 7.01-7.10 (m, 2H), 7.41 (d, J=5.4 Hz, 1H), 7.53(ddd, J=1.2, 4.7, 7.7 Hz, 1H), 7.96 (td, J=1.8. 7.8 Hz, 1H), 8.21 (dt,J=1.0, 7.9 Hz, 1H), 8.79 (ddd, J=0.9, 1.7, 4.7 Hz, 1H).

Preparation 16c:{5-fluoro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

A solution of{5-fluoro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester (0.050 g) in tetrahydrofuran (0.30 mL) was treatedwith 1.0 M aqueous lithium hydroxide solution (1.0 mL), and theresulting mixture was stirred at room temperature overnight. The mixturewas treated with 5.0 M aqueous sodium hydroxide solution (1.0 mL) andstirred at room temperature for 3 hours and then at 40° C. overnight.The mixture was acidified by the addition of aqueous hydrochloric acidsolution and concentrated under reduced pressure. The residue waspurified by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (2:3 to 19:1 by volume) to afford the titlecompound as a yellow solid (0.020 g).

¹H NMR (DMSO-d₆): δ 2.20 (s, 3H), 4.50 (s, 2H), 4.89 (s, 2H), 6.82 (m,2H), 7.27-7.33 (m, 2H), 7.37 (d, J=5.4 Hz, 1H), 7.71 (ddd, J=1.2, 4.7,7.6 Hz, 1H), 8.13 (td, J=1.8, 7.8 Hz, 1H), 8.19 (dt, J=1.1, 7.7 Hz, 1H),8.73 (ddd, J=0.9, 1.7, 4.7 Hz, 1H), 12.96 (br s, 1H).

MS: ESI (+ve) (Method A): 445 (M+H)⁺, Retention time 9.9 min.

Example 17{3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

Preparation 17a: 4-(4-chlorophenylsulfanyl)thiophene-3-carboxylic AcidMethyl Ester

A mixture of 4-(4-chlorophenylsulfanyl)thiophene-3-carboxylic acid (1.0g), sodium hydrogen carbonate (1.6 g), iodomethane (2.3 mL) andN,N-dimethylformamide (10 mL) was stirred was stirred at 40° C. for 5hours. The mixture was cooled to room temperature, diluted with water(100 mL) and the aqueous phase extracted with ethyl acetate. Thecombined organic extract was dried over magnesium sulfate andconcentrated under reduced pressure to afford the title compound as ayellow oil (1.0 g).

¹H NMR (DMSO-d₆): δ 3.77 (d, J=0.6 Hz, 3H), 6.96 (dd, J=0.6, 3.4 Hz,1H), 7.41-7.52 (m, 4H), 8.49 (dd, J=0.6, 3.4 Hz, 1H).

Preparation 17b: 4-(4-chlorobenzenesulfonyl)thiophene-3-carboxylic AcidMethyl Ester

The title compound was prepared by the method of Preparation 1b using4-(4-chlorophenylsulfanyl)thiophene-3-carboxylic acid methyl ester.

¹H NMR (DMSO-d₆): δ 3.7 (d, J=0.5 Hz, 3H), 7.67-7.73 (m, 2H), 7.88-7.93(m, 2H), 8.45 (dd, J=0.5, 3.4 Hz, 1H), 8.74 (dd, J=0.5, 3.4 Hz, 1H).

Preparation 17c: [4-(4-chlorobenzenesulfonyl)thiophen-3-yl]methanol

The title compound was prepared by the method of Preparation 6b using4-(4-chlorobenzenesulfonyl)thiophene-3-carboxylic acid methyl ester.

¹H NMR (CDCl₃): δ 4.62 (d, J=6.3 Hz, 2H), 4.69 (s, 1H), 7.37 (d, J=3.5Hz, 1H), 7.48-7.54 (m, 2H), 7.85-7.91 (m, 2H), 8.19 (d, J=3.4 Hz, 1H).

Preparation 17d: 4-(4-chlorobenzenesulfonyl)thiophene-3-carbaldehyde

The title compound was prepared by the method of Preparation 6c using[4-(4-chlorobenzenesulfonyl)thiophen-3-yl]methanol.

¹H NMR (DMSO-d₆): δ 7.67-7-73 (m, 2H), 7.97-8.02 (m, 2H), 8.69-8.72 (m,2H), 9.96 (s, 1H).

Preparation 17e:{3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using4-(4-chloro-benzenesulfonyl)thiophene-3-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 492 (M+H)⁺, Retention time 4.1 min.

Preparation 17f:{3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

A mixture of{3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticacid methyl ester (0.35 g) and tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (1.0 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined organic extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a white solid(0.30 g).

¹H NMR (DMSO-d₆): δ 2.13 (s, 3H), 3.94 (s, 2H), 4.89 (s, 2H), 6.35 (dd,J=2.5, 9.8 Hz, 1H), 6.80 (dt, J=2.5, 9.2 Hz, 1H), 6.96 (d, J=3.3 Hz,1H), 7.28 (dd, J=4.4, 8.9 Hz, 1H), 7.57-7.60 (m, 2H), 7.77-7.80 (m, 2H),8.60 (d, J=3.3 Hz, 1H), 13.0 (br s, 1H).

MS: ESI (+ve) (Method A): 478 (M+H)⁺, Retention time 11.4 min.

Example 18[3-(4-benzenesulfonylthiophen-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 18a:[3-(4-benzenesulfonylthiophen-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of{3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticacid (0.031 g), triethylamine (0.300 mL), palladium on charcoal (0.012g) and ethanol (5.0 mL) was stirred under an atmosphere of hydrogen at40° C. for 15 hours. The mixture was filtered through Celite and thefiltrate concentrated under reduced pressure. The residue was purifiedby preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (1:19 to 49:1 by volume) to afford the titlecompound as a pale yellow solid (0.024 g).

¹H NMR (DMSO-d₆): δ 2.07 (s, 3H), 3.89 (s, 2H), 4.80 (s, 2H), 6.39 (dd,J=2.5, 9.8 Hz, 1H), 6.77-6.82 (m, 2H), 7.28 (dd, J=4.4, 8.8 Hz, 1H),7.61-7.65 (m, 2H), 7.70-7.74 (m, 1H), 7.89-7.92 (m, 2H), 8.56 (d, J=3.4Hz, 1H), 13.0 (br s, 1H).

MS: ESI (+ve) (Method A): 444 (M+H)⁺, Retention time 10.8 min.

Example 19[5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]aceticAcid

Preparation 19a:[5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-phenylsulfonylthiophene-3-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.20 (s, 3H), 3.74 (s, 3H), 4.16 (s, 2H), 4.75 (s,2H), 6.49 (dd, J=2.5, 9.5 Hz, 1H), 6.57 (d, J=5.3 Hz, 1H), 6.82 (td,J=2.5, 9.9 Hz, 1H), 7.03 (dd, J=4.2, 9.0 Hz, 1H), 7.39 (d, J=5.0 Hz,1H), 7.52-7.57 (m, 2H), 7.59-7.64 (m, 1H), 8.01-8.05 (m, 2H).

MS: ESI (+ve) (Method B): 458 (M+H)⁺, Retention time 3.9 min.

Preparation 19b:[5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]aceticAcid

A mixture of[5-fluoro-3-(2-benzenesulfonylthiophen-3-ylmethyl)-2-methylindol-1-yl]aceticacid methyl ester (0.18 g), tetrahydrofuran (4.0 mL) and methanol (2.0mL) was treated with 1.0 M aqueous sodium hydroxide solution (2.0 mL),and the resulting mixture was stirred at room temperature for 1 hour.The mixture was acidified by the addition of 1.0 M aqueous hydrochloricacid solution and concentrated to low bulk under reduced pressure. Theresulting precipitate was collected by filtration, washed with water anddried to afford the title compound as a white solid (0.16 g).

¹H NMR (DMSO-d₆): δ 2.11 (s, 3H), 4.09 (s, 2H), 4.88 (s, 2H), 6.51-6.56(m, 2H), 6.78 (td, J=2.6, 9.2 Hz, 1H), 7.28 (dd, J=4.4, 8.9 Hz, 1H),7.59-7.65 (m, 2H), 7.67-7.73 (m, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.94-7.98(m, 2H), 12.95 (br s, 1H).

MS: ESI (+ve) (Method A): 444 (M+H)⁺, Retention time 10.9 min.

Example 20[5-fluoro-2-methyl-3-(2-phenylsulfamoylbenzyl)indol-1-yl]acetic Acid

Preparation 20a: [5-fluoro-2-methyl-3-(2-sulfobenzyl)indol-1-yl]aceticAcid Methyl Ester

A mixture of (5-fluoro-2-methylindol-1-yl) acetic acid methyl ester (1.0g), 2-formylbenzensulfonic acid sodium salt (0.94 g) and1,2-dichloroethane (15 mL) at 0° C. was treated dropwise with a mixtureof triethylsilane (4.3 mL), trifluoroacetic acid (1.0 mL) and1,2-dichloroethane (10 mL), and the resulting mixture was stirred atroom temperature for 6 hours. The mixture was extracted with ethylacetate and the combined organic extract was dried over sodium sulfate.The solvent was removed under reduced pressure and the residue purifiedby column chromatography on silica gel, eluting with a mixture ofmethanol and dichloromethane (0:1 to 1:9 by volume) to afford the titlecompound as a purple gum (1.3 g).

Preparation 20b:[3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic AcidMethyl Ester

A mixture of [5-fluoro-2-methyl-3-(2-sulfobenzyl)indol-1-yl]acetic acidmethyl ester (0.30 g) and dichloromethane (1.5 mL) was treated portionwise with phosphorus pentachloride (0.15 g), followed byN,N-dimethylformamide (0.070 mL), and the resulting mixture was heatedat reflux overnight. The mixture was cooled to room temperature,concentrated under reduced pressure and diluted with dichloromethane.The mixture was washed with water, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with dichloromethane to afford thetitle compound as a yellow solid (1.3 g).

MS: ESI (+ve) (Method B): 410 (M+H)⁺, Retention time 4.2 min.

Preparation 20c:[5-fluoro-2-methyl-3-(2-phenylsulfamoylbenzyl)indol-1-yl]acetic AcidMethyl Ester

A mixture of aniline (0.022 mL), triethylamine (0.051 mL) anddichloromethane (0.5 mL) was treated with[3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acidmethyl ester (0.10 g), and resulting mixture was stirred at roomtemperature for 4 days. The mixture was diluted with dichloromethane,washed with water and concentrated under reduced pressure to afford thetitle compound as a colourless gum (0.078 g).

MS: ESI (+ve) (Method B): 467 (M+H)⁺, Retention time 4.1 min.

Preparation 20d:[5-fluoro-2-methyl-3-(2-phenylsulfamoylbenzyl)indol-1-yl]acetic Acid

A mixture of[3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acidmethyl ester (0.078 g) and tetrahydrofuran (0.5 mL) was treated with 2.0M aqueous sodium hydroxide solution (1.0 mL), and the resulting mixturewas stirred at room temperature for 20 hours. The mixture was acidifiedby the addition of 2.0 M aqueous hydrochloric acid solution andconcentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (2:3 to 19:1 by volume) to afford the title compound as awhite solid (0.055 g).

¹H NMR (DMSO-d₆): δ 2.21 (s, 3H), 4.41 (s, 2H), 4.97 (s, 2H), 6.75 (dd,J=2.5, 9.8 Hz, 1H), 6.82-6.89 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 7.16 (d,J=7.8 Hz, 2H), 7.25 (t, J=7.3 Hz, 2H), 7.29-7.40 (m, 3H), 7.97 (dd,J=1.8, 7.5 Hz, 1H), 10.60 (br s, 1H), 12.95 (br s, 1H).

MS: ESI (+ve) (Method A): 453 (M+H)⁺, Retention time 11.1 min.

Example 21{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)benzyl]indol-1-yl}aceticAcid

Preparation 21a:{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)benzyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 20c using[3-(2-chlorosulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acidmethyl ester and N-methylaniline.

MS: ESI (+ve) (Method B): 481 (M+H)⁺, Retention time 4.2 min.

Preparation 21b:{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)benzyl]indol-1-yl}aceticAcid

A mixture of{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)benzyl]indol-1-yl}aceticacid methyl ester (0.10 g) and tetrahydrofuran (0.5 mL) was treated with2.0 M aqueous sodium hydroxide solution (2.0 mL), and the resultingmixture was stirred at room temperature for 15 hours. The mixture wasacidified by the addition of 2.0 M aqueous hydrochloric acid solutionand concentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (2:3 to 1:9 by volume) to afford the title compound as paleyellow solid (0.083 g).

¹HNMR (DMSO-d₆): δ 2.10 (s, 3H), 3.23 (s, 3H), 3.95 (s, 2H), 4.88 (s,2H), 6.73 (dd, J=2.5, 9.9 Hz, 1H), 6.82 (td, J=2.2, 9.1 Hz, 1H), 6.85(d, J=7.4 Hz, 1H), 7.32 (m, 8H), 7.79 (dd, J=2.0, 7.9 Hz, 1H).

MS: ESI (+ve) (Method A): 467 (M+H)⁺, Retention time 11.6 min.

Example 22[5-fluoro-3-(4-phenylsulfonylpyridin-3-ylmethyl)-2-methylindol-1-yl]aceticAcid

Preparation 22a: 4-phenylsulfonylpyridine-3-carbaldehyde

A mixture of 4-bromopyridine-3-carbaldehyde (0.90 g), benzenesulfinicacid sodium salt (4.0 g), copper (I) iodide (4.6 g) and1-methyl-2-pyrrolidinone (50 mL) was heated at 60° C. for 2 hours. Themixture was cooled to room temperature, diluted with ethyl acetate andfiltered through Celite. The filtrate was washed with water, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel, eluting with amixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) toafford the title compound as a yellow oil (1.9 g).

¹H NMR (CDCl₃): δ 7.56-7.74 (m, 3H), 7.88-7.98 (m, 3H), 9.05 (s, 1H),9.21 (s, 1H), 10.92 (s, 1H).

Preparation 22b:[5-fluoro-3-(4-phenylsulfonylpyridin-3-ylmethyl)-2-methylindol-1-yl]aceticAcid Methyl Ester

A mixture of triethylsilane (5.1 g), trifluoroacetic acid (3.1 g) and1,2-dichloroethane (20 mL) at −10° C. was treated dropwise with amixture of 4-phenylsulfonylpyridine-3-carbaldehyde (1.9 g),(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.66 g) and1,2-dichloroethane (20 mL), and the resulting mixture was stirred atroom temperature for 20 hours. The mixture was treated with additionaltriethylsilane (5.1 g) and trifluoroacetic acid (3.1 g), and stirred atroom temperature for 3 hours and then at 50° C. for 20 hours. Themixture was diluted with dichloromethane, washed with saturated aqueoussodium hydrogen carbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography on silica gel, eluting with a mixture ofcyclohexane and ethyl acetate (1:0 to 0:1 by volume), followed bytrituration with diethyl ether to afford the title compound as a yellowpowder (0.19 g).

¹H NMR (CDCl₃): δ 2.16 (s, 3H), 3.72 (s, 3H), 4.23 (s, 2H), 4.75 (s,2H), 6.25 (dd, J=2.6, 9.3 Hz, 1H), 6.81 (dt, J=2.6, 8.9 Hz, 1H), 7.03(dd, J=4.1, 8.9 Hz, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H),7.95 (d, J=7.6 Hz, 2H), 8.00 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 8.67 (d,J=5.0 Hz, 1H).

Preparation 22c:[5-fluoro-3-(4-phenylsulfonylpyridin-3-ylmethyl)-2-methylindol-1-yl]aceticAcid

A mixture of[5-fluoro-3-(4-phenylsulfonylpyridin-3-ylmethyl)-2-methylindol-1-yl]aceticacid methyl ester (0.19 g) and tetrahydrofuran (1.0 mL) was treated with2.0 M aqueous sodium hydroxide solution (3.0 mL), and the resultingmixture was stirred at room temperature for 3 hours. The mixture wasacidified by the addition of 1.0 M aqueous hydrochloric acid solution,and the resulting precipitate was collected by filtration to afford thetitle compound as a pale yellow powder (0.15 g).

¹H NMR (DMSO-d₆): δ 2.08 (s, 3H), 4.17 (s, 2H), 4.90 (s, 2H), 6.23 (dd,J=2.7, 9.8 Hz, 1H), 6.78 (td, J=2.6, 9.3 Hz, 1H), 7.31 (dd, J=4.5, 8.9Hz, 1H), 7.65 (t, J=7.6 Hz, 2H), 7.76 (t, J=7.5 Hz, 1H), 7.96-8.01 (m,3H), 8.08 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 12.91 (br s, 1H).

MS: ESI (+ve) (Method A): 439 (M+H)⁺, Retention time 10.0 min.

Example 23{5-fluoro-3-[3-(pyridine-3-sulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 23a: 3-(pyridine-3-sulfonyl)thiophene-2-carbaldehyde

A mixture of 3-chlorothiophene-2-carbaldehyde (0.16 g),pyridine-3-sulfinic acid sodium salt (0.30 g) and dimethyl sulfoxide(2.0 mL) was heated at 80° C. for 3 hours and then at 90° C. for 3hours. The mixture was diluted with water, extracted with ethyl acetateand the combined organic extract was dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford the title compoundas a grey solid (0.079 g).

¹H NMR (CDCl₃): δ 7.50-7.57 (m, 2H), 7.75 (dd, J=1.2, 5.2 Hz, 1H),8.23-8.28 (m, 1H), 8.88 (s, 1H), 9.20 (s, 1H), 10.64 (d, J=1.2 Hz, 1H).

Preparation 23b:{5-fluoro-3-[3-(pyridine-3-sulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

A mixture of triethylsilane (0.42 g), trifluoroacetic acid (0.25 g) and1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with amixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.055g), 3-(pyridine-3-sulfonyl)thiophene-2-carbaldehyde (0.075 g) and1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred atroom temperature for 20 hours. The mixture was treated with additionaltriethylsilane (0.42 g) and trifluoroacetic acid (0.25 g), and stirredat room temperature for 3 hours and then at 50° C. for 20 hours. Themixture was diluted with dichloromethane, washed with saturated aqueoussodium hydrogen carbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue purified bycolumn chromatography on silica gel, eluting with a mixture of diethylether and ethyl acetate (1:0 to 0:1 by volume), followed by triturationwith diethyl ether to afford the title compound as a white solid (0.027g).

¹H NMR (CDCl₃): δ 2.26 (s, 3H), 3.72 (s, 3H), 4.43 (s, 2H), 4.77 (s,2H), 6.67 (dd, J=2.4, 6.9 Hz, 1H), 6.83 (dt, J=2.5, 9.0 Hz, 1H), 7.03(dd, J=4.2, 8.8 Hz, 1H), 7.07 (d, J=5.7 Hz, 1H), 7.39-7.45 (m, 2H),8.14-8.18 (m, 1H), 8.79 (d, J=4.5 Hz, 1H), 9.13 (s, 1H).

Preparation 23c:{5-fluoro-3-[3-(pyridine-3-sulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[3-(pyridine-3-sulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester (0.025 g) and tetrahydrofuran (0.8 mL) was treatedwith 2.0 M aqueous sodium hydroxide solution (0.5 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasacidified by the addition of 1.0 M aqueous hydrochloric acid solution,extracted with ethyl acetate and the combined organic extract was driedover magnesium sulfate. The solvent was removed under reduced pressureand the residue triturated with diethyl ether to afford the titlecompound as a white solid (0.020 g).

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 4.45 (s, 2H), 4.92 (s, 2H), 6.72 (dd,J=2.5, 9.8 Hz, 1H), 6.82 (td, J=2.6, 9.1 Hz, 1H), 7.32 (dd, J=4.4, 8.8Hz, 1H), 7.40-7.44 (m, 2H), 7.63 (dd, J=4.8, 8.1 Hz, 1H), 8.35-8.39 (m,1H), 8.85 (dd, J=1.8, 4.9 Hz, 1H), 9.13-9.16 (m, 1H), 12.98 (br s, 1H).

MS: ESI (+ve) (Method A): 445 (M+H)⁺, Retention time 9.5 min.

Example 24{5-fluoro-2-methyl-3-[3-(Pyridine-4-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

Preparation of 24a: 3-(pyridin-4-ylsulfanyl)thiophene-2-carbaldehyde

A mixture of 4-mercaptopyridine (1.0 g), potassium carbonate (3.7 g) anddimethyl sulfoxide (10 mL) at 0° C. was treated with3-chlorothiophene-2-carbaldehyde (1.3 g), and the resulting mixture wasstirred at room temperature for 20 hours. The mixture was partitionedbetween ethyl acetate and water, and the organic phase was washed withwater and dried over magnesium sulfate. The solvent was removed underreduced pressure and the residue purified by column chromatography onsilica gel, eluting with a mixture of ethyl acetate and petroleum ether(1:9 to 3:2 by volume) to afford the title compound as yellow oil (1.3g).

¹HNMR (CDCl₃) δ 7.01 (m, 2H), 7.16 (d, J=5.0 Hz, 1H), 7.85 (dd, J=1.3,5.0 Hz, 1H), 8.44 (d, J=5.0 Hz, 2H), 10.12 (s, 1H).

Preparation of 24b:{5-fluoro-2-methyl-3-[3-(pyridin-4-ylsulfanyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

A mixture of 3-(pyridin-4-ylsulfanyl)thiophene-2-carbaldehyde (1.3 g),(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.3 g) and1,2-dichloroethane (30 mL) at −10° C. was treated with a mixture oftriethylsilane (5.8 mL), trifluoroacetic acid (2.4 mL) and1,2-dichloroethane (20 mL), and the resulting mixture was stirred atroom temperature for 48 hours. The mixture was diluted withdichloromethane, washed with aqueous sodium bicarbonate solution andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with ethyl acetate to afford thetitle compound as yellow foam (2.4 g).

¹HNMR (CDCl₃) δ 2.28 (s, 3H), 3.73 (s, 3H), 4.21 (s, 2H), 4.69 (s, 2H),6.81 (dd, J=1.6, 4.5 Hz, 2H), 6.87 (m, 1H), 7.02 (m, 2H), 7.08 (dd,J=2.4, 9.5 Hz, 1H), 7.20 (d, J=5.3 Hz, 1H), 8.28 (dd, J=1.6, 4.6 Hz,2H).

Preparation of 24c:{5-fluoro-2-methyl-3-[3-(pyridine-4-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

A mixture of5-fluoro-2-methyl-3-[3-(pyridin-4-ylsulfanyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester (0.20 g) and dichloromethane (2 mL) at 0° C. wastreated dropwise with a solution of 3-chloroperoxybenzoic acid (0.16 g)in dichloromethane (0.5 mL), and the resulting mixture was stirred atroom temperature for 18 hours. The mixture was cooled to 0° C., treatedwith additional 3-chloroperoxybenzoic acid (0.16 g) and stirred at 0° C.temperature for 1 hour. The mixture was partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution, and theaqueous phase was extracted with ethyl acetate. The combined organicphase was dried over sodium sulfate and concentrated under reducedpressure to afford a brown oil. The residue was purified by columnchromatography on a silica gel, eluting with a mixture ofdichloromethane and ethyl acetate (9:1 to 0:10 by volume). Furtherpurification by preparative reverse-phase HPLC, eluting with a mixtureacetonitrile and water (1:9 to 9:1 by volume) gave the title compound asa yellow solid (0.026 g).

MS: ESI (+ve) (Method B): 459 (M+H)⁺, Retention time 2.4 min.

Preparation 24d:{5-fluoro-2-methyl-3-[3-(pyridine-4-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

A mixture of{5-fluoro-2-methyl-3-[3-(pyridine-4-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester (0.026 g) and tetrahydrofuran (0.5 mL) was treatedwith 2.0 M aqueous sodium hydroxide solution (2.0 mL), and the resultingmixture was stirred at room temperature for 3 hours. The mixture wasacidified by the addition of 2.0 M aqueous hydrochloric acid solutionand concentrated under reduced pressure. The residue was purified bypreparative HPLC, eluting with a mixture of acetonitrile and water (1:19to 1:1 by volume) to afford the title compound as yellow solid (0.015g).

¹HNMR (CDCl₃) δ 1.76 (s, 3H), 3.39 (d, J=17.0 Hz, 1H), 4.39 (d, J=17.7Hz, 1H), 4.52 (d, J=17.7 Hz, 1H), 4.56 (d, J=17.0 Hz, 1H), 6.90 (m, 2H),7.11 (d, J=5.3 Hz, 1H), 7.22 (m, 1H), 7.42 (dd, J=8.3, 2.9 Hz, 1H), 7.49(d, J=5.3 Hz, 1H), 7.63 (dd, J=8.7, 5.0 Hz, 1H), 8.30 (m, 2H).

MS: ESI (+ve) (Method A): 445 (M+H)⁺, Retention time 6.1 min.

Example 25{3-[2-(3-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

Preparation 25a: 3-chlorobenzenesulfinic Acid Sodium Salt

A solution of 3-chlorobenzenesulfonyl chloride (3.0 g) in dioxane (40mL) was treated with a mixture of sodium hydrogen carbonate (2.7 g),sodium sulfite (3.6 g) and water (20 mL), and the resulting mixture wasstirred at 75° C. for 30 minutes. The mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wastriturated with ethanol to afford the title compound as a white solid(0.20 g).

Preparation 25b: 2-(3-chlorobenzenesulfonyl)pyridine-3-carbaldehyde

The title compound was prepared by the method of Preparation 5a using2-chloropyridine-3-carbaldehyde and 3-chlorobenzenesulfinic acid sodiumsalt.

¹H NMR (CDCl₃): δ 7.40-7.56 (m, 1H), 7.60-7.67 (m, 2H), 7.92-7.96 (m,1H), 8.02-8.04 (m, 1H), 8.40 (dd, J=1.7, 7.9 Hz, 1H), 8.71 (dd, J=1.7,4.6 Hz, 1H), 11.12 (d, J=0.8 Hz, 1H).

Preparation 25c:{3-[2-(3-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-(3-chlorobenzenesulfonyl)pyridine-3-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.30 (s, 3H), 3.77 (s, 3H), 4.63 (s, 2H), 4.83 (s,2H), 6.84 (dd, J=2.3, 9.5 Hz, 1H), 6.91 (dt, J=2.5, 9.1 Hz, 1H), 7.11(dd, J=4.1, 8.8 Hz, 1H), 7.22 (dd, J=4.6, 7.9 Hz, 1H), 7.37-7.41 (m,1H), 7.50-7.56 (m, 1H), 7.64 (ddd, J=1.1, 2.0, 8.0 Hz, 1H), 7.94-7.98(m, 1H), 8.05-8.06 (m, 1H), 8.31-8.33 (m, 1H).

MS: ESI (+ve) (Method B): 487 (M+H)⁺, Retention time 4.0 min.

Preparation 25d:{3-[2-(3-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

A mixture of{3-[2-(3-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticacid methyl ester (0.10 g) and tetrahydrofuran (5.0 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.31 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure and the pH adjusted to 4 by theaddition of 0.1 M aqueous hydrochloric acid solution. The mixture wasextracted with ethyl acetate and the combined extract was washed withsaturated aqueous sodium chloride solution and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuepurified by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (1:19 to 49:1 by volume) to afford the titlecompound as a white solid (0.085 g).

¹H NMR (DMSO-d₆): δ 2.24 (s, 3H), 4.53 (s, 2H), 4.93 (s, 2H), 6.84 (dt,J=2.5, 9.2 Hz, 1H), 6.88 (dd, J=2.5, 9.8 Hz, 1H), 7.34-7.37 (m, 1H),7.40 (dd, J=1.6, 8.0 Hz, 1H), 7.43-7.46 (m, 1H), 7.67-7.71 (m, 1H),7.82-7.86 (m, 1H), 7.93-7.95 (m, 2H), 8.33 (dd, J=1.6, 4.4 Hz, 1H), 13.1(br s, 1H).

MS: ESI (+ve) (Method A): 473 (M+H)⁺, Retention time 11.1 min.

Example 26 {5-chloro-3-[2-(benzenesulfonyl)pyridine-3-ylmethyl]-2-methylindol-1-yl}acetic Acid

Preparation 26a: (5-chloro-2-methylindol-1-yl)acetic Acid Methyl Ester

A mixture of (5-chloro-2-methylindol-1-yl)acetic acid (25 g), potassiumcarbonate (100 g) and N,N-dimethylformamide (220 mL) was treateddropwise with methyl bromoacetate (37 g), and the resulting mixture wasstirred at 60° C. for 2 days. The mixture was cooled to room temperatureand partitioned between water and ethyl acetate. The aqueous layer wasextracted with ethyl acetate and the combined organic solution waswashed with saturated aqueous sodium chloride solution, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting with a mixtureof dichloromethane and pentane (1:10 to 1:0 by volume) to afford thetitle compound as a white solid (27 g).

¹H NMR (CDCl₃): δ 2.36 (s, 3H), 3.72 (s, 3H), 4.74 (s, 2H), 6.23 (s,1H), 7.03-7.09 (m, 2H), 7.47 (d, J=1.5 Hz, 1H).

Preparation 26b:{5-chloro-3-[2-(benzenesulfonyl)pyridine-2-ylmethyl]-3-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using2-(benzenesulfonyl)pyridine-3-carbaldehyde and(5-chloro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.25 (s, 3H), 3.72 (s, 3H), 4.52 (s, 2H), 4.88 (s,2H), 7.01-7.08 (m, 2H), 7.36-7.40 (m, 3H), 7.65-7.70 (m, 3H), 7.95 (dt,J=1.5, 8.4 Hz, 2H), 8.30 (dd, J=1.6, 4.6 Hz, 1H).

Preparation 26c:{5-chloro-3-[2-(benzenesulfonyl)pyridine-2-ylmethyl]-3-methylindol-1-yl}aceticAcid

A mixture of{5-chloro-3-[2-(benzenesulfonyl)pyridin-2-ylmethyl]-3-methylindol-1-yl}aceticacid methyl ester (0.15 g) and tetrahydrofuran (1.3 mL) was treated with5.0 M aqueous sodium hydroxide solution (1.7 mL), and the resultingmixture was stirred at 40° C. for 2 hours. The mixture was acidified bythe addition of 5.0 M aqueous hydrochloric acid solution and extractedwith ethyl acetate. The combined organic extract was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (2:3 to 9:1 by volume) to afford the titlecompound as a white solid (0.23 g).

¹H NMR (DMSO-d₆): δ 2.23 (s, 3H), 4.51 (s, 2H), 4.95 (s, 2H), 7.00 (dd,J=2.2, 8.7 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.32-7.44 (m, 3H), 7.66 (m,2H), 7.76 (tt, J=1.3, 7.5 Hz, 1H), 7.97 (dt, J=1.6, 8.3 Hz, 2H), 8.33(dd, J=1.6, 4.5 Hz, 1H) 13.00 (br s, 1H).

MS: ESI (+ve) (Method A): 455 (M+H)⁺, Retention time 10.6 min.

Example 27{5-fluoro-3-[2-(2-chlorobenzenesulfonyl)pyridine-3-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 27a: 2-chlorobenzenesulfinic Acid Sodium Salt

A mixture of 2-chlorobenzenesulfonyl chloride (2.5 g) and dioxane (35mL) was treated with a mixture of sodium bicarbonate (2.0 g), sodiumsulfite (3.0 g) and water (17 mL), and the resulting mixture was heatedat 75° C. for 30 minutes. The mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was triturated withethanol, filtered and the filtrate concentrated under reduced pressure.The residue was triturated with acetonitrile to afford the titlecompound as a white solid (2.3 g).

¹H NMR (CD₃OD): δ 7.31 (dd, J=1.2, 4.8 Hz, 2H), 7.34-7.40 (m, 1H), 7.86(ddd, J=0.8, 1.2, 7.5 Hz, 1H).

Preparation 27b: 2-(2-chlorobenzenesulfonyl)pyridine-3-carbaldehyde

A mixture of 2-chlorobenzenesulfinic acid sodium salt (0.55 g),2-chloropyridine-carbaldehyde (0.35 g) and dimethyl sulfoxide (10 mL)was heated at 100° C. for 2 days. The mixture was cooled to roomtemperature and partitioned between water and dichloromethane. Theaqueous layer was extracted with dichloromethane and the combinedorganic solution was washed with saturated aqueous sodium chloridesolution, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with a mixture of ethyl acetate and pentane (0:1 to 3:2 byvolume) to afford the title compound as a white solid (0.089 g).

¹H NMR (CDCl₃): δ 7.49 (dd, J=1.6, 7.6 Hz, 1H) 7.55-7.67 (m, 3H), 8.39(dd, J=1.7, 7.9 Hz, 1H), 8.45 (dd, J=1.9, 7.6 Hz, 1H), 8.67 (dd, J=1.7,4.6 Hz, 1H), 11.20 (d, J=0.8 Hz, 1H).

Preparation 27c:{5-fluoro-3-[2-(2-chlorobenzenesulfonyl)pyridine-3-ylmethyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

A mixture of triethylsilane (0.76 mL), trifluoroacetic acid (0.61 mL)and 1,2-dichloroethane (3.0 mL) at −10° C. was treated dropwise with amixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.070g), 2-(2-chlorobenzenesulfonyl)-pyridine-3-carbaldehyde (0.089 g) and1,2-dichloroethane (6.0 mL), and the resulting mixture was stirred at−10° C. for 15 minutes and then at room temperature for 4 hours. Themixture was diluted with dichloromethane, washed with saturated aqueoussodium hydrogen carbonate solution and dried over sodium sulfate. Thesolvent was removed under reduced pressure and the residue purified bycolumn chromatography on silica gel, eluting with a mixture of ethylacetate and pentane (1:4 to 4:1 by volume). Further purification bycrystallisation from ethyl acetate and pentane gave the title compoundas a white solid (0.11 g).

¹H NMR (CDCl₃): δ 2.31 (s, 3H), 3.77 (s, 3H), 4.66 (s, 2H), 4.84 (s,2H), 6.91 (dddd, J=2.4, 2.5, 6.8, 8.9 Hz, 2H), 7.12 (dd, J=4.1, 8.7 Hz,1H), 7.23 (dd, J=4.5, 7.9 Hz, 1H), 7.40 (dd, J=1.0, 7.9 Hz, 1H),7.51-7.64 (m, 3H), 8.29 (dd, J=1.3, 4.5 Hz, 1H), 8.40 (dd, J=1.8, 7.5Hz, 1H).

Preparation 27d:{5-fluoro-3-[2-(2-chlorobenzenesulfonyl)pyridine-3-ylmethyl]-2-methylindol-1-yl}aceticAcid

A mixture of{5-fluoro-3-[2-(2-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester and tetrahydrofuran (1.0 mL) was treated with 5.0 Maqueous sodium hydroxide solution (1.2 mL), and the resulting mixturewas stirred at 45° C. for 4 hours. The mixture was acidified by theaddition of 5.0 M aqueous hydrochloric acid solution and extracted withdichloromethane. The combined organic extract was dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (2:3 to 9:1 by volume) to afford the titlecompound as a white solid (0.10 g).

¹H NMR (DMSO-d₆): δ 2.28 (s, 3H), 4.54 (s, 2H), 4.96 (s, 2H), 6.85 (dt,J=2.7, 9.3 Hz, 1H), 7.05 (dd, J=2.7, 9.7 Hz, 1H), 7.35-7.47 (m, 3H),7.68 (dt, J=1.4, 8.0 Hz, 2H), 7.76 (dt, J=1.6, 6.7 Hz, 1H), 8.25 (dd.J=1.8, 7.9 Hz, 1H), 8.29 (dd, J=1.7, 4.3 Hz, 1H), 12.95 (br s, 1H).

MS: ESI (+ve) (Method A): 473 (M+H)⁺, Retention time 10.7 min.

Example 28[3-(5-benzenesulfonylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 28a:5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carboxylic Acid MethylEster

A mixture of 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methylester (2.3 g), benzenesulfinic acid sodium salt (1.9 g) and dimethylsulfoxide (35 mL) was treated with bis[copper(I)triflate]benzene complex(3.3 g), and the resulting mixture was stirred at 65° C. for 1.5 hours.The mixture was cooled to 40° C. and filtered through Celite. Thefiltrate was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue purified bycolumn chromatography on silica gel, eluting with a mixture ofdichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford thetitle compound as a pale yellow solid (1.8 g).

MS: ESI (+ve) (Method B): 325 (M+H)⁺, Retention time 3.5 min.

Preparation 28b:5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carboxylic Acid

A mixture of 5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carboxylicacid methyl ester (1.4 g) and tetrahydrofuran (20 mL) was treated with1.0 M aqueous lithium hydroxide solution (2.2 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, pH adjusted to 4 by the addition of0.1 M aqueous hydrochloric acid solution and extracted with ethylacetate. The combined extract was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate and concentrated underreduced pressure to afford the title compound as a pale yellow solid(1.3 g).

¹H NMR (CDCl₃): δ 0.2.62 (s, 3H), 7.52-7.66 (m, 3H), 8.02-8.05 (m, 2H),9.21 (s, 1H).

MS: ESI (+ve) (Method B): 311 (M+H)⁺, Retention time 2.4 min.

Preparation 28c:5-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-yl)methanol

A mixture of 5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carboxylicacid (0.99 g), dichloromethane (50 mL) and N,N-dimethylformamide (0.2mL) was treated with oxalyl chloride (0.83 mL), and the resultingreaction mixture was stirred at room temperature for two hours. Themixture was concentrated under reduced pressure and the residue wasdissolved in a mixture of acetonitrile (20 mL) and tetrahydrofuran (30mL). The mixture was cooled to −78° C. and treated with a 2.0 M solutionof sodium borohydride in N,N-dimethylformamide (1.6 mL). The mixture waswarmed to −50° C. over 2 hours, diluted with 1.0 M aqueous hydrochloricacid solution and concentrated under reduced pressure. The residue wasdiluted with ethyl acetate, washed with water and dried over magnesiumsulfate. The solvent was removed under reduced pressure to afford thetitle compound as a yellow oil (0.59 g).

¹H NMR (DMSO-d₆): δ 2.61 (s, 3H), 4.66 (d, J=6.1 Hz, 2H), 5.36 (t, J=6.1Hz, 1H), 7.62-7.68 (m, 3H), 8.00-8.03 (m, 2H), 9.12 (s, 1H).

MS: ESI (+ve) (Method B): 297(M+H)⁺, Retention time 3.0 min.

Preparation 28d:5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carbaldehyde

A mixture of5-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-yl)methanol (0.42 g)and dichloromethane (100 mL) was treated with Dess-Martin periodinane(0.72 g), and the resulting mixture was stirred at 0° C. for 30 min. Themixture was filtered through Celite and the filtrate concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0to 0.1 by volume) to afford the title compound as a pale yellow oil(0.30 g).

¹H NMR (CDCl₃): δ 0.2.64 (s, 3H), 7.54-7.60 (m, 3H), 7.98-8.01 (m, 2H),9.25 (s, 1H), 10.21 (s, 1H).

MS: ESI (+ve) (Method B): 295 (M+H)⁺, Retention time 2.8 min.

Preparation 28e:[3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.20 (s, 3H), 2.23 (s, 3H), 3.73 (s, 3H), 4.32 (s,2H), 4.74 (s, 2H), 6.55 (dd, J=2.5, 9.6 Hz, 1H), 6.81 (dd, J=2.5, 9.1Hz, 1H), 7.00 (dd, J=4.2, 8.9 Hz, 1H), 7.53-7.59 (m, 2H), 7.64-7.69 (m,1H), 7.90-7.93 (m, 2H), 9.08 (s, 1H).

MS: ESI (+ve) (Method B): 500 (M+H)⁺, Retention time 4.1 min.

Preparation 28f:[3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]aceticAcid

A mixture of[3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.23 g) and tetrahydrofuran (30 mL) was treated with1.0 M aqueous lithium hydroxide solution (0.93 mL), and the resultingmixture was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure, the pH adjusted to 4 by theaddition of 0.1 M aqueous hydrochloric acid solution and extracted withethyl acetate. The combined extract was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by preparativereverse-phase HPLC, eluting with a mixture of acetonitrile and water(1:19 to 49:1 by volume) to afford the title compound as a yellow solid(0.20 g).

MS: ESI (+ve) (Method B): 486 (M+H)⁺, Retention time 3.8 min.

Preparation 28g:[3-(5-benzenesulfonylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of[3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid (0.20 g), ethanol (12 mL) and water (12 mL) was treated with RaneyNickel 2800 (0.050 g), and the resulting reaction mixture was stirred at60° C. for 45 minutes. The mixture was filtered through Celite and thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative reverse-phase HPLC, eluting with a mixture ofacetonitrile and water (1:19 to 49:1 by volume) to afford the titlecompound as an off-white solid (0.058 g).

¹H NMR (DMSO-d₆): δ 2.09 (s, 3H), 4.35 (s, 2H), 4.87 (s, 2H), 6.40 (dd,J=2.5, 9.9 Hz, 1H), 6.78 (dd, J=2.5, 9.2 Hz, 1H), 7.27 (dd, J=4.3, 8.8Hz, 1H), 7.68 (m, 2H), 7.79 (tt, J=1.1, 7.6 Hz, 1H), 8.07 (m, 2H), 9.24(s, 1H), 9.40 (s, 1H).

MS: ESI (+ve) (Method A): 440 (M+H)⁺, Retention time 9.7 min.

Example 29[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-chloro-2-methylindol-1-yl]aceticAcid

Preparation 29a:[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-chloro-2-methylindol-1-yl]aceticAcid Methyl Ester

A mixture of triethylsilane (2.7 g), trifluoroacetic acid (1.6 g) anddichloroethane (8.0 mL) at −20° C. was treated dropwise with a mixtureof (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.36 g),3-phenylsulphonyl-2-thiophenealdehyde (0.39 g) and dichloroethane (8.0mL), and the resulting mixture was warmed to room temperature over aperiod of 1.5 hours. The mixture was treated with additionaltriethylsilane (2.7 g) and trifluoroacetic acid (1.6 g) and then stirredat room temperature for 1 hour. The mixture was diluted with saturatedaqueous sodium hydrogen carbonate solution and extracted withdichloromethane. The combined organic extract was washed with saturatedaqueous sodium chloride solution, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with a mixture of dichloromethaneand ethyl acetate (1:0 to 0:1 by volume) to afford the title compound(0.55 g).

MS: ESI (+ve) (Method B): 474 (M+H)⁺, Retention time 4.1 min.

Preparation 29b:[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-chloro-2-methylindol-1-yl]aceticAcid

A mixture of[3-(3-benzenesulfonylthiophen-2-ylmethyl)-5-chloro-2-methylindol-1-yl]aceticacid methyl ester (0.47 g), 1.0 M aqueous lithium hydroxide solution(2.0 mL) and tetrahydrofuran (2.0 mL) was stirred at room temperaturefor 1 hour. The mixture was acidified with 1.0 M aqueous hydrochloricacid solution and extracted with ethyl acetate. The combined organicextract was dried using a phase separation cartridge and concentratedunder reduced pressure. The residue was purified by crystallisation froma mixture of pentane and ethyl acetate to afford the title compound as awhite powder (0.39 g).

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 4.41 (s, 2H), 4.93 (s, 2H), 6.88 (d,J=2.0 Hz, 1H), 6.98 (dd, J=2.0, 8.7 Hz, 1H), 7.33 (s, 1H), 7.35 (d,J=5.5 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.61-7.67 (m, 2H), 7.69-7.74 (m,1H), 7.98-8.02 (m, 2H).

MS: ESI (+ve) (Method A): 459 (M+H)⁺, Retention time 11.2 min.

Example 30{5-fluoro-2-methyl-3-[2-(methyl-phenylsulfamoyl)pyridin-3-ylmethyl]indol-1-yl}aceticAcid

Preparation 30a: 2-phenylsulfamoylnicotinic Acid Methyl Ester

A mixture of 2-mercaptonicotinic acid methyl ester (1.4 g),dichloromethane (50 mL) and 1.0 M aqueous hydrochloric acid solution (50mL) at −10° C. was treated with sodium hypochlorite (8% in water, 50 mL)over a period of 5 minutes, and the resulting mixture was warmed to 0°C. over a period 15 minutes. The phases were separated and the organicphase was treated with 4 A molecular sieves and aniline (1.5 g), and theresulting mixture was stirred at room temperature for 1.5 hours. Themixture was filtered and the filtrate was washed with saturated aqueoussodium hydrogen carbonate solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue purified bycrystallisation from a mixture of cyclohexane and dichloromethane toafford the title compound (1.8 g).

MS: ESI (+ve) (Method B): 293 (M+H)⁺, Retention time 3.0 min.

Preparation 30b: 2-(methylphenylsulfamoyl)nicotinic Acid Methyl Ester

A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.8 g),acetonitrile (100 mL) and potassium carbonate (1.9 g) was treated with amixture of methyl bromide (1.5 mL) and acetonitrile (6.0 mL), and theresulting mixture was stirred at room temperature for 24 hours. Themixture was concentrated under reduced pressure, triturated withdichloromethane and filtered. The filtrate was concentrated underreduced pressure to afford the title compound as a tan oil (1.5 g).

MS: ESI (+ve) (Method B): 307 (M+H)⁺, Retention time 3.4 min.

Preparation 30c: 3-hydroxymethylpyridine-2-sulfonic AcidMethylphenylamide

A mixture of 2-(methylphenylsulfamoyl)nicotinic acid methyl ester (1.5g) and tetrahydrofuran (50 mL) at −78° C. was treated with a 1.0 Msolution of lithium aluminium hydride in tetrahydrofuran (10 mL), andthe resulting mixture was stirred at −78° C. for 1 hour and then at roomtemperature for 2 hours. The mixture was diluted with water, extractedwith ethyl acetate and the combined organic extract was dried overmagnesium sulfate. The solvent was removed under reduced pressure andthe residue was purified by column chromatography on silica gel, elutingwith a mixture of dichloromethane and methanol (1:0 to 19:1 by volume)to afford the title compound (0.25 g).

MS: ESI (+ve) (Method B): 279 (M+H)⁺, Retention time 3.0 min.

Preparation 30d: 3-formylpyridine-2-sulfonic Acid Methylphenylamide

A mixture of 3-hydroxymethylpyridine-2-sulfonic acid methylphenylamide(0.25 g), chloroform (20 mL) and manganese (IV) oxide (3.9 g) wasstirred at room temperature for 2 hours. The mixture was treated withadditional manganese (IV) oxide (1.6 g) and stirred at room temperaturefor a further 2 hours. The mixture was filtered through hyflo and thefiltrate was concentrated under reduced pressure to afford the titlecompound (0.10 g).

MS: ESI (+ve) (Method B): 277 (M+H)⁺, Retention time 3.4 min.

Preparation 30e:{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)-pyridin-3-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 29a using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and3-formylpyridine-2-sulfonic acid methylphenylamide.

MS: ESI (+ve) (Method B): 482 (M+H)⁺, Retention time 4.2 min.

Preparation 30f:{5-fluoro-2-methyl-3-[2-(methylphenyl-sulfamoyl)pyridin-3-ylmethyl]indol-1-yl}aceticAcid

A mixture of{5-fluoro-2-methyl-3-[2-(methylphenylsulfamoyl)pyridin-3-ylmethyl]indol-1-yl}aceticacid methyl ester (0.14 g), 1.0 M aqueous sodium hydroxide solution (1.0mL) and methanol (10 mL) was stirred at room temperature for 1.5 hours.The mixture was diluted with 1.0 M aqueous hydrochloric acid solutionand concentrated under reduced pressure. The residue was diluted with1.0 M aqueous hydrochloric acid solution and the resulting precipitatewas collected by filtration and dried to give the title compound as awhite solid (0.10 g).

¹H NMR (DMSO-d₆): δ 2.17 (s, 3H), 3.53 (s, 3H), 4.23 (s, 2H), 4.93 (s,2H), 6.78-6.89 (m, 2H), 7.21-7.39 (m, 5H), 7.41-7.50 (m, 3H), 8.50 (dd,J=1.4, 4.5 Hz, 1H).

MS: ESI (+ve) (Method A): 468 (M+H)⁺, Retention time 11.3 min.

Example 31{5-chloro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

Preparation 31a: 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde

A mixture of 3-bromothiophenecarbaldehyde (5.0 g), dimethyl sulfoxide(50 mL) and 4-fluorophenyl sodium sulfinate (5.2 g) was stirred at 100°C. for 3 hours. Additional 4-fluorophenyl sodium sulfinate (1.9 g) wasadded and the mixture was stirred at 100° C. for 18 hours. The mixturewas cooled to room temperature, diluted with water and extracted withethyl acetate. The combined organic extract was washed with water andsaturated aqueous sodium hydrogen carbonate solution and dried overmagnesium sulfate. The solvent was removed under reduced pressure andthe residue was purified by column chromatography on silica gel, elutingwith a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume)to afford the title compound (4.4 g).

¹H NMR (DMSO-d₆): δ 7.48-7.55 (m, 2H), 7.66 (d, J=5.2 Hz, 1H), 8.18-8.25(m, 3H), 10.51 (d, J=1.2 Hz, 1H)

Preparation 31b:{5-chloro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methyl-indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 29a using3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde and(5-chloro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 492 (M+H)⁺, Retention time 4.3 min.

Preparation 31c:{5-chloro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 30f using{5-chloro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.28 (s, 3H), 4.49 (s, 2H), 5.00 (s, 2H), 6.86 (d,J=2.0 Hz, 1H), 7.05 (dd, J=2.0, 8.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H),7.45 (d, J=5.4 Hz, 1H), 7.49 (d, J=5.4 Hz, 1H), 7.53 (t, J=8.8 Hz, 2H),8.15 (m, 2H).

MS: ESI (+ve) (Method A): 478 (M+H)⁺, Retention time 11.4 min.

Example 32{5-chloro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

Preparation 32a: 3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde

A mixture of pyridine-2-sulfinate sodium salt (8.5 g),3-bromothiophene-2-carbaldehyde (6.5 g) and dimethyl sulfoxide (50 mL)(split equally into four microwave vials) was heated by microwaveirradiation at 125° C. for 45 minutes. The combined mixtures werediluted with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate solution and saturated aqueous sodium chloridesolution and dried over magnesium sulfate. The solvent was removed underreduced pressure and the residue was purified by column chromatographyon silica gel, eluting with a mixture of dichloromethane and ethylacetate (1:0 to 0:1 by volume) to afford the title compound as a yellowsolid (0.55 g).

¹H NMR (CDCl₃): δ 7.52 (ddd, J=0.8, 4.7, 7.7 Hz, 1H), 7.58 (d, J=5.2 Hz,1H), 7.69 (dd, J=1.0, 4.2 Hz, 1H), 7.98 (dt, J=1.7, 7.8 Hz, 1H), 8.23(d, J=7.9 Hz, 1H), 8.70 (d, J=4.7 Hz, 1H), 10.7 (d, J=1.0 Hz 1H).

Preparation 32b:{5-chloro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 29a using3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and(5-chloro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 475 (M+H)⁺, Retention time 3.9 min.

Preparation 32c:{5-chloro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 29b using{5-chloro-2-methyl-3-[3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.22 (s, 3H), 4.52 (s, 2H), 4.93 (s, 2H), 6.99 (dd,J=2.1, 8.7 Hz, 1H), 7.06 (dd, J=2.0 Hz, 1H), 7.29 (d, J=5.3 Hz, 1H),7.35 (d, J=8.7 Hz, 1H), 7.38 (d, J=5.3 Hz, 1H), 7.72 (ddd, J=1.2, 4.6,7.6 Hz, 1H), 8.13 (dt, J=1.7, 7.8 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.76(m, 1H).

MS: ESI (+ve) (Method A): 461 (M+H)⁺, Retention time 10.4 min.

Example 33{5-fluoro-2-methyl-3-[2-(pyrimidine-5-sulfonyl)benzyl]indol-1-yl}aceticAcid

Preparation 33a:5-[2-(tert-butyl-dimethylsilanyloxymethyl)phenylsulfanyl]pyrimidine

A mixture of 2-(tert-butyl-dimethylsilanyloxymethyl)benzenethiol (5.6g), 5-bromopyridine (4.6 g), cesium carbonate (11 g) andN-methylpyrrolidone (25 mL) was heated at 100° C. for 2 hours. Themixture was diluted with water and extracted with diethyl ether. Thecombined organic extract was washed with water and saturated aqueoussodium chloride solution and dried over magnesium sulfate. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel, eluting with a mixture ofcyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the titlecompound as a light brown oil (7.0 g).

MS: ESI (+ve) (Method B): 333 (M+H)⁺, Retention time 4.7 min.

Preparation 33b:5-[2-(tert-butyl-dimethylsilanyloxymethyl)benzenesulfonyl]pyrimidine

A mixture of5-[2-(tert-butyl-dimethylsilanyloxymethyl)phenylsulfanyl]pyrimidine (8.1g) and dichloromethane (200 mL) at 0° C. was treated portion wise with3-chloroperoxybenzoic acid (15 g), and the resulting mixture was stirredat room temperature for 4 hours. The mixture was partitioned betweendichloromethane and saturated solution of sodium hydrogen carbonate. Theorganic phase was washed with saturated aqueous sodium chloridesolution, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to8.5:2.5 by volume) to afford the title compound as a pale brown oil (7.0g).

MS: ESI (+ve) (Method B): 438 (M+H)⁺, Retention time 3.7 min.

Preparation 33c: [2-(pyrimidine-5-sulfonyl)phenyl]methanol

A mixture of5-[2-(tert-butyl-dimethylsilanyloxymethyl)benzenesulfonyl]pyrimidine(2.1 g) and tetrahydrofuran (2.0 mL) was treated with 1.0 M solution oftetrabutylammonium fluoride in tetrahydrofuran (7.5 mL), and theresulting mixture was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate, washed with saturatedaqueous sodium chloride solution and dried over magnesium sulfate. Thesolvent was removed under reduced pressure to afford the title compounda pale brown solid (0.64 g).

MS: ESI (+ve) (Method B): 251 (M+H)⁺, Retention time 2.4 min.

Preparation 33d: 2-(pyrimidine-5-sulfonyl)benzaldehyde

The title compound was prepared by the method of Preparation 30d using[2-(pyrimidine-5-sulfonyl)phenyl]methanol.

MS: ESI (+ve) (Method B): 247 (M−H)⁻, Retention time 2.6 min.

Preparation 33e:{5-fluoro-2-methyl-3-[2-(pyrimidine-5-sulfonyl)benzyl]indol-1-yl}aceticAcid Methyl Ester

A mixture of (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.50g), 2-(pyrimidine-5-sulfonyl)benzaldehyde (0.35 g) and dichloroethane(50 mL) at −70° C. was treated sequentially with triethylsilane (2.5 g)and trifluoroacetic acid (0.81 g), and the resulting mixture was stirredat −70° C. for 1 hour. The mixture was slowly warmed to room temperatureand stirred at this temperature for 18 hours. The mixture was dilutedwith saturated aqueous sodium hydrogen carbonate solution and the phaseswere separated. The organic phase was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 to 2:3by volume) to afford the title compound as a brown oil (0.12 g).

MS: ESI (+ve) (Method B): 454 (M+H)⁺, Retention time 3.6 min.

Preparation 33f:{5-fluoro-2-methyl-3-[2-(pyrimidine-5-sulfonyl)benzyl]indol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 29b using{5-fluoro-2-methyl-3-[2-(pyrimidine-5-sulfonyl)benzyl]indol-1-yl}aceticacid methyl ester.

¹H NMR (CD₃OD): δ 2.64 (s, 3H), 4.39 (s, 2H), 4.86 (s, 2H), 6.10 (dd,J=2.5, 9.9 Hz, 1H), 6.70 (dt, J=2.5, 9.1 Hz, 1H), 7.04 (dd, J=4.4, 8.9Hz, 1H), 7.42 (dd, J=0.7, 7.4 Hz, 1H), 7.58-7.70 (m, 2H), 8.34 (dd,J=1.5, 7.8 Hz, 1H), 8.82 (s, 2H), 9.07 (s, 1H).

MS: ESI (+ve) (Method A): 440 (M+H)⁺, Retention time 9.6 min.

Example 34[3-(5-benzenesulfonylthiazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 34a: 4-bromomethyl-5-chlorothiazole

A mixture of 4-methyl-5-chlorothiazole (2.8 g), carbon tetrachloride(100 mL), N-bromosuccinimide (4.9 g) and dibenzoyl peroxide (0.25 g) washeated at reflux for 3 hours. The mixture was cooled to roomtemperature, filtered and the filtrate concentrated under reducedpressure to afford the title compound as a red oil (4.4 g).

Preparation 34b: 5-chlorothiazole-4-carbaldehyde

A mixture of 4-bromomethyl-5-chlorothiazole (4.4 g), 4 A molecularsieves (44 g) and acetonitrile (100 mL) at 0° C., was treated portionwise with N-methylmorpholine oxide (4.9 g), and the resulting mixturewas stirred at room temperature for 18 hours. The mixture was filteredthrough hyflo and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel, elutingwith a mixture of cyclohexane and ethyl acetate (1:0 to 3:2 by volume)to afford the title compound as a white solid (1.1 g).

¹H NMR (CDCl₃): δ 8.74 (s, 1H), 10.6 (s, 1H).

Preparation 34c: 5-benzenesulfonylthiazole-4-carbaldehyde

The title compound was prepared by the method of Preparation 5a using5-chlorothiazole-4-carbaldehyde and phenylsulfinic acid sodium salt.

¹H NMR (CDCl₃): δ 7.57-7.63 (m, 2H), 7.66-7.71 (m, 1H), 8.07-8.11 (m,2H), 8.98 (s, 1H), 10.42 (s, 1H).

MS: ESI (+ve) (Method B): 254 (M+H)⁺, Retention time 9.6 min.

Preparation 34d:[3-(5-benzenesulfonylthiazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and5-benzenesulfonylthiazole-4-carbaldehyde in dichloromethane.

Preparation 34e:[3-(5-benzenesulfonylthiazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

The title compound was prepared by the method of Preparation 29b using[3-(5-benzenesulfonylthiazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.16 (s, 3H), 4.28 (s, 2H), 4.29 (s, 2H), 6.67 (dt,J=2.5, 9.1 Hz, 1H), 6.75 (dd, J=2.5, 10.3 Hz, 1H), 7.07 (dd, J=4.5, 8.8Hz, 1H), 7.56-7.63 (m, 2H), 7.65-7.71 (m, 2H), 7.88-7.93 (m, 2H), 9.23(s, 1H).

MS: ESI (+ve) (Method A): 445 (M+H)⁺, Retention time 10.4 min.

Example 35{5-fluoro-2-methyl-3-[5-(pyridine-2-sulfonyl)thiazol-4-ylmethyl]indol-1-yl}aceticAcid

Preparation 35a: 5-(pyridine-2-sulfonyl)thiazole-4-carbaldehyde

The title compound was prepared by the method of Preparation 5a using5-chloro-thiazole-4-carbaldehyde and pyridine-2-sulfinic acid sodiumsalt.

MS: ESI (+ve) (Method B): 257 (M+H)⁺, Retention time 2.1 min.

Preparation 35b:{5-fluoro-2-methyl-3-[5-(pyridine-2-sulfonyl)thiazol-4-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and5-(pyridine-2-sulfonyl)thiazole-4-carbaldehyde.

MS: ESI (+ve) (Method B): 460 (M+H)⁺, Retention time 3.6 min.

Preparation 35c:{5-fluoro-2-methyl-3-[5-(pyridine-2-sulfonyl)thiazol-4-ylmethyl]indol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 29b using{5-fluoro-2-methyl-3-[5-(pyridine-2-sulfonyl)thiazol-4-ylmethyl]indol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.21 (s, 3H), 4.34 (s, 2H), 4.83 (s, 2H), 6.75 (m,2H), 7.19 (dd, J=4.4, 8.8 Hz, 1H), 7.62 (ddd, J=1.4, 4.7, 7.3 Hz, 1H),8.00-8.09 (m, 2H), 8.59-8.62 (m, 1H), 9.30 (s, 1H), 12.9 (br s, 1H).

MS: ESI (+ve) (Method A): 446 (M+H)⁺, Retention time 9.3 min.

Example 36[3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic Acid

Preparation 36a:[3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic AcidMethyl Ester

A mixture of triethylsilane (0.71 g), trifluoroacetic acid (0.53 g) and1,2-dichloroethane (2.0 mL) at −10° C. was treated dropwise with amixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.091g), 2-benzenesulfonylbenzaldehyde (0.12 g) and 1,2-dichloroethane (3.0mL), and the resulting mixture was stirred at −10° C. for 15 minutes andthen at room temperature for 2 hours. The mixture was diluted withdichloromethane, washed with saturated aqueous sodium hydrogen carbonatesolution and dried over magnesium sulfate. The solvent was removed underreduced pressure and the residue purified by column chromatography onsilica gel, eluting with a mixture of cyclohexane and dichloromethane(1:1 to 0:1 by volume) to afford the title compound as a colourless gum(0.17 g).

MS: ESI (+ve) (Method B): 452 (M+H)⁺, Retention time 4.1 min.

Preparation 36b:[3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic Acid

A mixture of[3-(2-benzenesulfonylbenzyl)-5-fluoro-2-methylindol-1-yl]acetic acidmethyl ester (0.17 g), tetrahydrofuran (3.0 mL) and methanol (1.5 mL)was treated with 1.0 M aqueous sodium hydroxide solution (1.5 mL), andthe resulting mixture was stirred at room temperature for 2 hours. Themixture was acidified by the addition of 1.0 M aqueous hydrochloric acidsolution (1.5 mL) and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate, dried over magnesium sulfate andconcentrated under reduced pressure to afford the title compound as acream solid (0.13 g).

¹H NMR (DMSO-d₆): δ 2.06 (s, 3H), 4.14 (s, 2H), 4.94 (s, 2H), 6.19 (dd,J=2.6, 7.3 Hz, 1H), 6.81 (dt, J=2.6, 9.1 Hz, 1H), 6.89 (m, 1H), 7.33(dd, J=4.3, 9.1 Hz, 1H), 7.51 (m, 2H), 7.67 (m, 2H), 7.75 (m, 1H), 7.95(m, 2H), 8.23 (m, 1H), 12.99 (br s, 1H).

MS: ESI (+ve) (Method A): 438 (M+H)⁺, Retention time 11.0 min.

MS: ESI (+ve) (Method B): 438 (M+H)⁺, Retention time 3.8 min.

Example 37[3-(3-benzenesulfonyl-5-methylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 37a: 3-benzenesulfonyl-5-methylthiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 7a using3-bromo-5-methylthiophene-2-carbaldehyde and phenylsulfinic acid sodiumsalt.

¹H NMR (CDCl₃): δ 2.52 (d, J=1.0 Hz, 3H), 7.17 (d, J=1.0 Hz, 1H),7.53-7.68 (m, 3H), 7.94-7.99 (m, 2H), 10.55 (s, 1H).

Preparation 37b:[3-(3-benzenesulfonyl-5-methylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 29a using3-benzenesulfonyl-5-methylthiophene-2-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.26 (s, 6H), 3.74 (s, 3H), 4.38 (s, 2H), 4.78 (s,2H), 6.65 (dd, J=2.5, 9.4 Hz, 1H), 6.84 (td, J=2.5, 9.0 Hz, 1H),7.01-7.08 (m, 2H), 7.52-7.66 (m, 3H), 7.97-8.02 (m, 2H).

Preparation 37c:[3-(3-benzenesulfonyl-5-methylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

The title compound was prepared by the method of Preparation 29b using[3-(3-benzenesulfonyl-5-methylthiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.20 (s, 3H), 2.26 (s, 3H), 4.40 (s, 2H), 4.93 (s,2H), 6.71 (dd, J=2.5, 9.8 Hz, 1H), 6.85 (td, J=2.5, 9.2 Hz, 1H), 7.08(d, J=1.3 Hz, 1H), 7.35 (dd, J=4.4, 8.9 Hz, 1H), 7.65-7.71 (m, 2H),7.72-7.77 (m, 1H), 8.01-8.05 (m, 2H).

MS: ESI (+ve) (Method A): 458 (M+H)⁺, Retention time 11.3 min.

Example 38{5-fluoro-2-methyl-3-[5-methyl-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

Preparation 38a:5-methyl-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 7a using3-bromo-5-methylthiophene-2-carbaldehyde and pyridine-2-sulfinate sodiumsalt.

¹H NMR (DMSO-d₆): δ 2.54 (d, J=1.0 Hz, 3H), 7.49-7.53 (m, 1H), 7.97 (td,J=1.7, 7.8, Hz, 1H), 8.21 (dt, J=1.0, 7.9, Hz, 1H), 8.70 (ddd, J=0.9,1.7, 4.7 Hz, 1H), 10.58 (s, 1H).

Preparation 38b:5-fluoro-2-methyl-3-[5-methyl-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

A mixture of (5-fluor-2-methylindol-1-yl)acetic acid methyl ester (0.059g), 5-methyl-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde (0.071 g)and dichloroethane (1.5 mL) at 0° C. was treated dropwise with asolution of triethylsilane (0.46 g) and trifluoroacetic acid (0.27 g) indichloroethane (1.0 mL), and the resulting mixture was stirred at roomtemperature for 1 hour and then at 60° C. for 1 hour. The mixture wascooled to room temperature and additional triethylsilane (2.7 g) andtrifluoroacetic acid (1.6 g) were added, and the resulting mixture wasstirred at room temperature for 1 hour. The mixture was partitionedbetween dichloromethane and saturated aqueous sodium hydrogen carbonatesolution. The phases were separated and the organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel, eluting with amixture of cyclohexane and ethyl acetate (1:0 to 2:3 by volume) toafford the title compound (0.060

¹H NMR (CDCl₃): δ 2.34 (s, 3H), 2.26 (d, J=1.1, 3H), 3.75 (s, 3H), 4.63(s, 2H), 4.80 (s, 2H), 6.87 (dt, J=2.5, 9.0, 1H), 6.95 (dd, J=2.4, 9.5Hz, 1H), 7.04-7.08 (m, 2H), 7.50-7.54 (m, 1H), 7.95 (dt, J=1.7, 7.7 Hz,1H), 8.19 (dt, J=1.0, 7.9, Hz, 1H), 8.78-8.81 (m, 1H).

MS: ESI (+ve) (Method B): 473 (M+H)⁺, Retention time 3.9 min.

Preparation 38c:{5-fluoro-2-methyl-3-[5-methyl-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 29b using5-fluoro-2-methyl-3-[5-methyl-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]indol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.25 (s, 3H), 2.26 (d, J=1.1 Hz, 3H), 4.50 (s, 2H),4.95 (s, 2H), 6.86 (dd, J=2.5, 9.1 Hz, 1H), 6.90 (dd, J=2.4, 10.1 Hz,1H), 7.02 (d, J=1.3 Hz, 1H), 7.35 (dd, J=4.4, 8.8 Hz, 1H), 7.76 (ddd,J=1.3, 4.7, 7.5 Hz, 1H), 8.17 (td, J=1.7, 7.6 Hz, 1H), 8.23 (dt, J=1.1,7.9 Hz, 1H), 8.79 (ddd, J=0.9, 1.7, 4.7 Hz, 1H).

MS: ESI (+ve) (Method A): 459 (M+H)⁺, Retention time 10.4 min.

Example 39[5-fluoro-2-methyl-3-(2-phenylsulfamoylpyridin-3-ylmethyl)indol-1-yl]aceticAcid

Preparation 39a:2-{phenyl-[2-(trimethylsilanyl)ethoxymethyl]sulfamoyl}nicotinic AcidMethyl Ester

A mixture of 2-phenylsulfamoylnicotinic acid methyl ester (1.1 g),N,N-diisopropylethylamine (1.9 mL) and dichloromethane at 0° C. wastreated with 2-(trimethylsilyl)ethoxymethyl chloride (0.67 mL), and theresulting mixture was stirred at room temperature overnight. The mixturewas cooled to 0° C., treated with additional(trimethylsilyl)ethoxymethyl chloride (0.30 mL), and stirred at roomtemperature for 5 hours. The mixture was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with a mixture of dichloromethane and cyclohexane (0:1 to1:0 by volume) to afford the title compound (1.6 g).

¹H NMR (CDCl₃): δ-0.07-0.02 (m, 9H), 0.87-0.95 (m, 2H), 3.75-3.82 (m,2H), 3.85 (s, 3H), 5.33 (s, 2H), 7.15-7.29 (m, 5H), 7.53 (ddd, J=0.9,4.7, 7.8 Hz, 1H), 7.92-7.97 (m, 1H), 8.72-8.76 (m, 1H).

Preparation 39b: 3-hydroxymethylpyridine-2-sulfonic Acidphenyl[2-(trimethylsilanyl)ethoxymethyl]amide

The title compound was prepared by the method of Preparation 30c using(2-{phenyl-[2-(trimethylsilanyl)ethoxymethyl]sulfamoyl}nicotinic acidmethyl ester.

¹H NMR (CDCl₃): δ 0.00-0.04 (m, 9H), 0.91-0.98 (m, 2H), 2.74 (t, J=7.1Hz, 1H), 3.79-3.85 (m, 2H), 4.79 (d, J=7.1 Hz, 2H), 5.33 (s, 2H),7.27-7.34 (m, 5H), 7.50 (dd, J=4.7, 7.8 Hz, 1H), 7.94 (dd, J=1.6, 7.8Hz, 1H), 8.6 (dd, J=1.7, 4.7 Hz, 1H).

Preparation 39c: 3-formylpyridine-2-sulfonic Acidphenyl[2-(trimethylsilanyl)ethoxymethyl]amide

The title compound was prepared by the method of Preparation 30d using3-hydroxymethylpyridine-2-sulfonic acidphenyl[2-(trimethylsilanyl)ethoxymethyl]amide.

¹H NMR (CDCl₃): δ 0.00-0.03 (m, 9H), 0.89-0.97 (m, 2H), 3.76-3.84 (m,2H), 5.34 (s, 2H), 7.28-7.36 (m, 5H), 7.64 (ddd, J=0.8, 4.7, 7.9 Hz,1H), 8.35 (dd, J=1.8, 7.9 Hz, 1H), 8.86 (dd, J=1.8, 4.7 Hz, 1H), 10.56(d, J=0.8 Hz, 1H).

Preparation 39d:[5-fluoro-2-methyl-3-(2-phenylsulfamoylpyridin-3-ylmethyl)indol-1-yl]aceticAcid Methyl Ester

A mixture of triethylsilane (3.1 mL), trifluoroacetic acid (0.88 mL) anddichloroethane (12 mL) at −15° C. was treated dropwise with a mixture of3-formylpyridine-2-sulfonic acidphenyl[2-(trimethylsilanyl)ethoxymethyl]amide (0.55 g),(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.29 g) anddichloroethane (18 mL), and the resulting mixture was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure and the residue was dissolved in dichloromethane. The mixturewas washed with saturated aqueous sodium hydrogen carbonate solution,dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel, elutingwith a mixture of dichloromethane, cyclohexane, ethyl acetate andmethanol (9:1:0:0 to 0:0:9:1 by volume) to afford the title compound(0.20 g).

MS: ESI (+ve) (Method B): 466 (M−H)⁻, Retention time 3.9 min.

Preparation 39e:[5-fluoro-2-methyl-3-(2-phenylsulfamoylpyridin-3-ylmethyl)indol-1-yl]aceticAcid

A mixture of[5-fluoro-2-methyl-3-(2-phenylsulfamoylpyridin-3-ylmethyl)indol-1-yl]aceticacid methyl ester (0.20 g), 1.0 M aqueous sodium hydroxide solution(0.50 mL) and methanol (10 mL) was stirred at room temperature for 3hours. The mixture was concentrated under reduced pressure and theresidue was diluted with 1.0 M aqueous hydrochloric acid solution. Theresulting precipitate was collected by filtration and purified bypreparative reverse-phase HPLC, eluting with a mixture of acetonitrileand water (3:7 to 9:1 by volume) to afford the title compound (0.020 g).

¹H NMR (DMSO-d₆): δ 2.25 (s, 3H), 4.44 (s, 2H), 4.98 (s, 2H), 6.84-6.94(m, 2H), 7.00-7.08 (m, 1H), 7.23-7.28 (m, 4H), 7.30-7.34 (m, 1H),7.36-7.45 (m, 2H), 8.43 (dd, J=1.5, 4.5 Hz, 1H), 10.71 (s, 1H), 13.02(br s, 1H).

MS: ESI (+ve) (Method A): 454 (M+H)⁺, Retention time 10.2 min.

Example 40{3-[2-(2,4-dichlorobenzenesulfonyl)benzyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

Preparation 40a: 2-(2,4-dichlorobenzenesulfonyl)benzaldehyde

A mixture of 3-chloroperoxybenzoic acid (77% in water, 5.5 g) anddichloromethane (10 mL) was treated dropwise with a mixture of2-(2,4-dichlorophenylsulfanyl)benzaldehyde (2.3 g) and dichloromethane(10 mL), and the resulting mixture was stirred at room temperature for 2hours. The mixture was partitioned between dichloromethane and saturatedaqueous sodium hydrogen carbonate solution. The phases were separatedand the organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and dried over potassium carbonate. The solvent wasremoved under reduced pressure and the residue purified by columnchromatography on silica gel, eluting with a mixture of cyclohexane anddichloromethane (1:0 to 1:2 by volume) to afford the title compound as awhite solid (0.55 g).

¹H NMR (CDCl₃): δ 7.46 (d, J=2.0 Hz, 1H), 7.53 (dd, J=2.0, 8.6 Hz 1H),7.76-7.81 (m, 2H), 8.00-8.05 (m, 1H), 8.25-8.31 (m, 1H), 8.33 (d, J=8.6Hz, 1H), 10.64 (s, 1H).

MS: ESI (+ve) (Method B): 315 (M+H)⁺, Retention time 3.9 min.

Preparation 40b:{3-[2-(2,4-dichlorobenzenesulfonyl)benzyl]-5-fluoro-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 27c using2-(2,4-dichlorobenzenesulfonyl)benzaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.14 (s, 3H), 3.75 (s, 3H), 4.12 (s, 2H), 4.77 (s,2H), 6.42 (dd, J=2.5, 9.5 Hz, 1H), 6.84 (td, J=2.5, 9.0 Hz, 1H),6.96-6.99 (m, 1H), 7.04 (dd, J=4.2, 8.8 Hz, 1H), 7.38-7.44 (m, 3H), 7.48(d, J=2.0 Hz, 1H), 8.32-8.38 (m, 2H).

MS: ESI (+ve) (Method B): 520 (M+H)⁺, Retention time 4.4 min

Preparation 40c:{3-[2-(2,4-dichlorobenzenesulfonyl)benzyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 19b using{3-[2-(2,4-dichlorobenzenesulfonyl)benzyl]-5-fluoro-2-methylindol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.11 (s, 3H), 4.07 (s, 2H), 4.94 (s, 2H), 6.27 (dd,J=2.5, 9.9 Hz, 1H), 6.82 (td, J=2.5, 9.2, Hz, 1H), 7.00 (dd, J=1.6, 7.5Hz, 1H), 7.32 (dd, J=4.4, 8.9 Hz, 1H), 7.51-7.60 (m, 2H), 7.72 (dd,J=2.1, 8.6 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 8.26 (dd, J=1.8, 7.7 Hz, 1H,8.35 (d, J=8.6 Hz, 1H).

MS: ESI (+ve) (Method A): 506 (M+H)⁺, Retention time 12.2 min.

Example 41{5-fluoro-3-[2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

Preparation 41a: 2-(4-fluorobenzenesulfonyl)benzaldehyde

The title compound was prepared by the method of Preparation 33b using2-[(4-fluorophenyl)thio]benzaldehyde.

¹H NMR (CDCl₃): δ 7.18-7.25 (m, 2H), 7.73-7.78 (m, 2H), 7.89-7.96 (m,2H), 8.01-8.05 (m, 1H), 8.16-8.20 (m, 1H), 10.85 (d, J=0.64 Hz, 1H).

Preparation 41b:{5-fluoro-3-[2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 27c using2-(4-fluorobenzenesulfonyl)benzaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

¹H NMR (CDCl₃): δ 2.15 (s, 3H), 3.76 (s, 3H), 4.22 (s, 2H), 4.78 (s,2H), 6.31 (dd, J=2.5, 9.5, Hz, 1H), 6.83 (td, J=2.5, 9.0 Hz, 1H),6.93-6.98 (m, 1H), 7.05 (dd, J=4.2, 8.8 Hz, 1H), 7.21 (t, J=8.5 Hz, 2H),7.35-7.43 (m, 2H), 7.92-7.98 (m, 2H), 8.27-8.31 (m, 1H).

Preparation 41c:{5-fluoro-3-[2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 5c using{5-fluoro-3-[2-(4-fluorobenzenesulfonyl)benzyl]-2-methylindol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.11 (s, 3H), 4.16 (s, 2H), 4.95 (s, 2H), 6.15 (dd,J=2.5, 9.8 Hz, 1H), 6.81 (td, J=2.5, 9.2 Hz, 1H), 6.92-6.97 (m, 1H),7.30-7.37 (m, 1H), 7.44-7.55 (m, 4H), 7.99-8.05 (m, 2H), 8.19-8.25 (m,1H).

MS: ESI (+ve) (Method A): 456 (M+H)⁺, Retention time 11.1 min.

Example 42[3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

Preparation 42a: 4-benzenesulfonylthiazole-5-carbaldehyde

A mixture of 4-chlorothiazole-5-carbaldehyde (0.15 g), benzenesulfinicacid sodium salt (0.25 g) and dimethyl sulfoxide (7.0 mL) was stirred at100° C. for 30 minutes. The mixture was cooled to room temperature,poured onto ice/water (50 mL) and extracted with ethyl acetate. Thecombined organic extract was washed with saturated aqueous sodiumchloride solution and dried over magnesium sulfate. The solvent wasremoved under reduced pressure to afford the title compound as a tan oil(0.23 g).

¹H NMR (CDCl₃): δ 7.57-7.63 (m, 2H), 7.67-7.73 (m, 1H), 8.11-8.14 (m,2H), 8.95 (d, J=0.9 Hz, 1H), 10.83 (d, J=0.9 Hz, 1H).

Preparation 42b:[3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.2g), 4-benzenesulfonylthiazole-5-carbaldehyde (0.23 g) and1,2-dichloroethane (7.0 mL) at 0° C. was treated dropwise with a mixtureof triethylsilane (2.2 mL), trifluoroacetic acid (0.6 mL) and1,2-dichloroethane (2.0 mL), and the resulting mixture was stirred atroom temperature overnight. The mixture was cooled to 0° C. and dilutedwith saturated aqueous sodium hydrogen carbonate solution. The phaseswere separated and the organic phase was dried over magnesium sulfateand concentrated under reduced pressure. The residue purified by columnchromatography on silica gel, eluting with a mixture of ethyl acetateand dichloromethane (0:1 to 1:4 by volume) to afford the title compoundas a white foam (0.20 g).

MS: ESI (+ve) (Method B): 459 (M+H)⁺, Retention time 3.7 min.

Preparation 42c:[3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of lithium hydroxide (0.10 g), tetrahydrofuran (1.0 mL) andwater (1.0 mL) was treated[3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.20 g), and the resulting mixture was stirred atroom temperature for 30 minutes. The mixture was diluted with water,concentrated to low bulk under reduced pressure and acidified by theaddition of 1.0 M aqueous hydrochloric acid solution. The resultingprecipitate was collected by filtration, washed with water and dried toafford the title compound as a white solid (0.19 g).

¹H NMR (DMSO-d₆): δ 2.30 (s, 3H), 4.70 (s, 2H), 4.96 (s, 2H), 6.90 (td,J=2.5, 9.2 Hz, 1H), 7.08 (dd, J=2.5, 9.8 Hz, 1H), 7.39 (dd, J=4.4, 8.9Hz, 1H), 7.66-7.72 (m, 2H), 7.74-7.80 (m, 1H), 8.04-8.09 (m, 2H), 8.89(s, 1H), 13.02 (br s, 1H).

MS: ESI (+ve) (Method A): 445 (M+H)⁺, Retention time 10.1 min.

MS: ESI (+ve) (Method B): 445 (M+H)⁺, Retention time 3.5 min.

Example 43{5-fluoro-2-methyl-3-[4-(pyridine-2-sulfonyl)thiazol-5-ylmethyl]indol-1-yl}aceticAcid

Preparation 43a: 4-(pyridine-2-sulfonyl)thiazole-5-carbaldehyde

The title compound was prepared by the method of Preparation 42a using4-chlorothiazole-5-carbaldehyde and pyridine-2-sulfinate sodium salt.

¹H NMR (CDCl₃): δ 7.54-7.59 (m, 1H), 7.99-8.06 (m, 1H), 8.34-8.38 (m,1H), 8.67-8.71 (m, 1H), 8.96 (d, J=0.9 Hz, 1H), 10.85 (d, J=0.8 Hz, 1H).

Preparation 43b:{5-fluoro-2-methyl-3-[4-(pyridine-2-sulfonyl)thiazol-5-ylmethyl]indol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 42b using4-(pyridine-2-sulfonyl)thiazole-5-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 460 (M+H)⁺, Retention time 3.5 min.

Preparation 43c:{5-fluoro-2-methyl-3-[4-(pyridine-2-sulfonyl)thiazol-5-ylmethyl]indol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 42c using{5-fluoro-2-methyl-3-[4-(pyridine-2-sulfonyl)thiazol-5-ylmethyl]indol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.36 (s, 3H), 4.77 (s, 2H), 4.97 (s, 2H), 6.91 (td,J=2.5, 9.2 Hz, 1H), 7.30 (dd, J=2.5, 9.9 Hz, 1H), 7.39 (dd, J=4.4, 8.9Hz, 1H) 7.76-7.81 (m, 1H), 8.19-8.24 (m, 1H), 8.28 (dt, J=1.1, 7.9 Hz,1H), 8.75-8.78 (m, 1H), 8.87 (s, 1H), 12.98 (br s, 1H).

MS: ESI (+ve) (Method A): 446 (M+H)⁺, Retention time 9.1 min.

MS: ESI (+ve) (Method B): 446 (M+H)⁺, Retention time 3.3 min.

Example 44{3-[5-chloro-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

Preparation 44a:5-chloro-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 42a using3,5-dichlorothiophene-2-carbaldehyde and pyridine-2-sulfinate sodiumsalt.

¹H NMR (CDCl₃): δ 7.53-7.58 (m, 1H), 7.76 (s, 1H), 7.99 (td, J=1.7, 7.8Hz, 1H), 8.17-8.22 (m, 1H), 8.73-8.76 (m, 1H), 10.08 (s, 1H).

Preparation 44b:{3-[5-chloro-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 42b using5-chloro-3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 493 (M+H)⁺, Retention time 4.0 min.

Preparation 44c:{3-[5-chloro-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticAcid

The title compound was prepared by the method of Preparation 42c using{3-[5-chloro-3-(pyridine-2-sulfonyl)thiophen-2-ylmethyl]-5-fluoro-2-methylindol-1-yl}aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.29 (s, 3H), 4.23 (s, 2H), 4.84 (s, 2H), 6.89 (td,J=2.5, 9.2 Hz, 1H), 7.16 (dd, J=2.5, 9.9 Hz, 1H), 7.36 (dd, J=4.4, 8.9Hz, 1H), 7.65-7.73 (m, 1H), 7.85 (s, 1H), 8.10-8.14 (m, 2H), 8.70 (dt,J=1.3, 4.7 Hz, 1H).

MS: ESI (+ve) (Method A): 479 (M+H)⁺, Retention time 11.1 min.

MS: ESI (+ve) (Method B): 479 (M+H)⁺, Retention time 3.7 min.

Example 45[3-(3-benzenesulfonyl-5-chlorothiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]-aceticAcid

Preparation 45a: 3-benzenesulfonyl-5-chlorothiophene-2-carbaldehyde

The title compound was prepared by the method of Preparation 42a using3,5-dichlorothiophene-2-carbaldehyde and benzenesulfinic acid sodiumsalt.

¹H NMR (CDCl₃): δ 7.55-7.61 (m, 3H), 7.65-7.71 (m, 1H), 7.99-8.03 (m,2H), 10.05 (s, 1H).

Preparation 45b:[3-(3-benzenesulfonyl-5-chlorothiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 42b using3-benzenesulfonyl-5-chlorothiophene-2-carbaldehyde and(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.

MS: ESI (+ve) (Method B): 492 (M+H)⁺, Retention time 4.2 min.

Preparation 45c:[3-(3-benzenesulfonyl-5-chlorothiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

The title compound was prepared by the method of Preparation 42c using[3-(3-benzenesulfonyl-5-chlorothiophen-2-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester.

¹H NMR (DMSO-d₆): δ 2.28 (s, 3H), 4.21 (s, 2H), 4.92 (s, 2H), 6.90 (td,J=2.6, 9.2 Hz, 1H), 7.16 (dd, J=2.6, 9.8 Hz, 1H), 7.39 (dd, J=4.4, 8.9Hz, 1H), 7.58-7.64 (m, 2H), 7.67-7.73 (m, 1H), 7.89-7.94 (m, 3H).

MS: ESI (+ve) (Method A): 478 (M+H)⁺, Retention time 12.0 min.

MS: ESI (+ve) (Method B): 478 (M+H)⁺, Retention time 3.9 min.

Example 46[3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]aceticAcid

Preparation 46a: (3,4-dichloroisothiazol-5-yl)methanol

A mixture of 3,4-dichloroisothiazole-5-carboxylic acid (2.0 g) andtoluene (20 mL) was treated with thionyl chloride (5.0 mL) andN,N-dimethylformamide (0.5 mL), and the resulting mixture was heated at100° C. for 16 hours. The mixture was concentrated under reducedpressure and the residue was dissolved in tetrahydrofuran (5.0 mL). Themixture was cooled to −78° C. and treated dropwise over a period of 1hour with a 2.0 M solution of sodium borohydride inN,N-dimethylformamide (8.5 mL). The mixture was stirred at −78° C. for 5minutes, diluted with 1.0 M aqueous hydrochloric acid solution andextracted with ethyl acetate. The combined organic extract was washedwith saturated aqueous sodium chloride solution, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting with a mixtureof cyclohexane and dichloromethane (1:0 to 0:1 by volume) to afford thetitle compound as a pale yellow solid (1.1 g).

¹H NMR (CDCl₃): δ 4.96 (s, 2H).

Preparation 46b: 3,4-dichloroisothiazole-5-carbaldehyde

A mixture of (3,4-dichloroisothiazol-5-yl)methanol (1.1 g), chloroform(150 mL) and manganese dioxide (4.7 g) was stirred at 40° C. for 20hours. The mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure to afford the title compound as ayellow solid (0.62 g).

¹H NMR (CDCl₃): δ 10.07 (s, 1H).

Preparation 46c: 4-benzenesulfonyl-3-chloroisothiazole-5-carbaldehyde

A mixture of 3,4-dichloroisothiazole-5-carbaldehyde (0.087 g),benzenesulfinic acid sodium salt (0.078 g) and dimethyl sulfoxide (3.0mL) was stirred at room temperature for 3.5 hours. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution anddried over magnesium sulfate. The solvent was removed under reducedpressure and the residue was purified by column chromatography on silicagel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1by volume) to afford the title compound as a colourless oil (0.093 g).

¹H NMR (CDCl₃): δ 7.61-7.65 (m, 2H), 7.69-7.75 (m, 1H), 8.03-8.07 (m,2H), 10.76 (s, 1H).

Preparation 46d:[3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

The title compound was prepared by the method of Preparation 1c using(5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and4-benzenesulfonyl-3-chloroisothiazole-5-carbaldehyde.

MS: ESI (+ve) (Method B): 493 (M+H)⁺, Retention time 4.6 min.

Preparation 47e:[3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

A mixture of[3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.065 g), tetrahydrofuran (20 mL) and 1.0 M aqueouslithium hydroxide solution (4.0 mL) was stirred at room temperature for5 minutes. The mixture was concentrated under reduced pressure,acidified by the addition of 1.0 M aqueous hydrochloric acid solutionand extracted with ethyl acetate. The combined organic extract waswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by preparative reverse-phase HPLC, eluting with a mixtureof acetonitrile and water (1:19 to 19:1 by volume) to afford the titlecompound as a white solid (0.050 g).

¹H NMR (CDCl₃): δ 2.29 (s, 3H), 4.76 (s, 2H), 4.97 (s, 2H), 6.91-6.96(dt, J=2.5, 9.2 Hz, 1H), 7.22-7.26 (dd, J=2.5, 9.8 Hz, 1H), 7.42-7.45(m, 1H), 7.71-7.76 (m, 2H), 7.81-7.85 (m, 1H), 8.18-8.20 (m, 2H), 13.5(br s, 1H).

MS: ESI (+ve) (Method A): 479 (M+H)⁺, Retention time 11.5 min.

MS: ESI (+ve) (Method B): 479 (M+H)⁺, Retention time 3.9 min.

Example 47 [3-(4-benzenesulfonylisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic Acid

Preparation 47a:[3-(4-benzenesulfonylisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid

The title compound was prepared by the method of Preparation 18a using[3-(4-benzenesulfonyl-3-chloroisothiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid.

MS: ESI (+ve) (Method B): 445 (M+H)⁺, Retention time 37 min.

Example 48[3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]aceticAcid

Preparation 48a: 5-bromo-1-methyl-1H-imidazole-4-carbaldehyde

A mixture of 1-methyl-1H-imidazole-4-carbaldehyde (0.50 g),N-bromosuccinimide (0.89 g) and chloroform (7.0 mL) was heated at refluxfor 2 hours. The mixture was cooled to 0° C., diluted with saturatedaqueous sodium carbonate solution (10 mL) and extracted withdichloromethane. The combined organic extract was dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel, eluting with a mixtureof ethyl acetate and dichloromethane (0:1 to 7:10 by volume) to affordthe title compound as a white solid (0.37 g).

¹H NMR (CDCl₃): δ 3.70 (s, 3H), 7.66 (s, 1H), 9.89 (s, 1H).

Preparation 48b: 5-benzenesulfonyl-1-methyl-1H-imidazole-4-carbaldehyde

A mixture of benzenesulfinic acid sodium salt (0.065 g),5-bromo-1-methyl-1H-imidazole-4-carbaldehyde (0.037 g) and dimethylsulfoxide (2.0 mL) was heated by microwave irradiation at 180° C. for 10minutes. The mixture was treated with additional benzenesulfinic acidsodium salt (0.065 g), and heated by microwave irradiation at 180° C.for 40 minutes. The mixture was diluted with ethyl acetate, washed withwater and dried over magnesium sulfate. The solvent was removed underreduced pressure and the residue was triturated with cyclohexane toafford a yellow solid. The solid was collected by filtration, washedwith cyclohexane and dried to afford the title compound (0.030 g).

MS: ESI (+ve) (Method B): 251 (M+H)⁺, Retention time 2.7 min.

Preparation 48c:[3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticAcid Methyl Ester

A mixture of triethylsilane (0.17 g), trifluoroacetic acid (0.10 g) and1,2-dichloroethane (5.0 mL) at −5° C. was treated dropwise with amixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.022g), 5-benzenesulfonyl-1-methyl-1H-imidazole-4-carbaldehyde (0.030 g) and1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred atroom temperature overnight and then at 45° C. for 2 hours. The mixturewas diluted with dichloromethane, washed with saturated aqueous sodiumhydrogen carbonate solution and dried using a phase separationcartridge. The solvent was removed under reduced pressure and theresidue was purified by column chromatography on silica gel, elutingwith a mixture of ethyl acetate and dichloromethane (0:1 to 2:5 byvolume) to afford the title compound as a yellow oil (0.027 g).

MS: ESI (+ve) (Method B): 456 (M+H)⁺, Retention time 3.5 min.

Preparation 48d:[3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]aceticAcid

A mixture of[3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]aceticacid methyl ester (0.027 g), methanol (3.0 mL) and 1.0 M aqueous sodiumhydroxide solution (0.12 mL) was stirred at room temperature for 1 hour.The mixture was treated with tetrahydrofuran (1.0 mL) and 1.0 M aqueoussodium hydroxide solution (0.24 mL), and stirred at room temperature for4 hours and then at 40° C. for 30 minutes. The mixture was concentratedunder reduced pressure and acidified by the addition of 1.0 M aqueoushydrochloric acid solution. The resulting precipitate was collected byfiltration, washed with water and dried to afford the title compound asa white solid (0.024 g).

¹H NMR (DMSO-d₆): δ 2.36 (s, 3H), 3.62 (s, 3H), 4.26 (s, 2H), 4.94 (s,2H), 6.78-6.85 (m, 1H), 7.26 (dd, J=2.6, 10.9 Hz, 1H), 7.31 (dd, J=4.5,8.9 Hz, 1H), 7.50-7.56 (m, 2H), 7.63-7.68 (m, 1H), 7.71-7.75 (m, 1H),7.85 (d, J=1.1 Hz, 1H), 7.81 (s, 1H), 12.99 (br s, 1H).

MS: ESI (+ve) (Method A): 440 (M+H)⁺, Retention time 9.3 min.

MS: ESI (+ve) (Method B): 442 (M+H)⁺, Retention time 3.5 min.

Biological Methods

Compounds of the invention were tested using the following biologicaltest method to determine their ability to displace PGD₂ from the CRTH2receptor.

CRTH2 Radioligand Binding Assay

The receptor binding assay is performed in a final volume of 200 μLbinding buffer [10 mM BES (pH 7.4), 1 mM EDTA, 10 mM manganese chloride,0.01% BSA] and 1 nM [³H]-PGD₂ (Amersham Biosciences UK Ltd). Ligands areadded in assay buffer containing a constant amount of DMSO (1% byvolume). Total binding is determined using 1% by volume of DMSO in assaybuffer and non-specific binding is determined using 10 μM of unlabeledPGD₂ (Sigma). Human embryonic kidney (HEK) cell membranes (3.5 μg)expressing the CRTH2 receptor are incubated with 1.5 mg wheatgermagglutinin SPA beads and 1 nM [³H]-PGD₂ (Amersham Biosciences UK Ltd)and the mixture incubated for 3 hours at room temperature. Bound[³H]-PGD₂ is detected using a Microbeta TRILUX liquid scintillationcounter (Perkin Elmer). Compound IC₅₀ value is determined using a6-point dose response curve in duplicate with a semi-log compounddilution series. IC₅₀ calculations are performed using Excel and XLfit(Microsoft), and this value is used to determine a K_(i) value for thetest compound using the Cheng-Prusoff equation.

GTPγS Functional Assay

The GTP□S Assay is performed in a final volume of 200 mL assay buffer(20 mM HEPES pH 7.4, 10 mM MgCl₂, 100 mM NaCl, 10 μg/mL saponin). DMSOconcentrations are kept constant at 1% by volume. Human embryonic kidney(HEK) cell membranes (3.5 μg) expressing the CRTH2 receptor areincubated with the compounds for 15 min at 30° C. prior to addition ofPGD₂ (30 nM final concentration) and GTP (10 μM final concentration).The assay solutions are then incubated for 30 minutes at 30° C.,followed by addition of [³⁵S]-GTPγS (0.1 nM final concentration). Theassay plate is than shaken and incubated for 5 minutes at 30° C.Finally, SPA beads (Amersham Biosciences, UK) are added to a finalconcentration of 1.5 mg/well and the plate shaken and incubated for 30minute at 30° C. The sealed plate is centrifuged at 1000 g for 10 minsat 30° C. and the bound [³⁵S]-GTPγS is detected on Microbetascintillation counter (Perkin Elmer). Compound IC₅₀ value is determinedusing a 6-point dose response curve in duplicate with a semi-logcompound dilution series. IC₅₀ calculations are performed using Exceland XLfit (Microsoft), and this value is used to determine a Ki valuefor the test compound using the Cheng-Prusoff equation.

Biological Results

All compounds of the Examples above were tested in the CRTH2 radioligandbinding assay described above; the compounds had a K_(i) value of lessthan 2 μM in the binding assay. For example, Examples 1, 16, 21 and 26had K_(i) values of 1.5, 2.4, 0.6 and 4.5 nM respectively. Examples 1,16 and 26, were tested in the GTPγS functional assay, and had K_(i)values of less than 10 nM.

We claim:
 1. A compound that is an indole derivative of formula (I), oris a pharmaceutically acceptable salt of formula (I):

wherein X is —SO₂— or *—SO₂NR³— wherein the bond marked with an asteriskis attached to Ar¹; R¹ is hydrogen, fluoro, chloro, CN or CF₃; R² ishydrogen, fluoro or chloro; R³ is hydrogen, C₁-C₈alkyl orC₃-C₇cycloalkyl; Ar¹ is phenyl or a 5- or 6-membered heteroaryl groupselected from furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyland pyrazinyl, wherein the phenyl or heteroaryl groups are optionallysubstituted by one or more substituents independently selected fromfluoro, chloro, CN, C₃-C₇cycloalkyl, —O(C₁-C₄alkyl) and C₁-C₆alkyl, thelatter two groups being optionally substituted by one or more fluoroatoms; and Ar² is phenyl or a 5- or 6-membered heteroaryl group selectedfrom pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyland pyrazinyl, wherein the phenyl or heteroaryl groups are optionallysubstituted by one or more substituents independently selected fromfluoro, chloro, CN, C₃-C₇cycloalkyl, —O(C₁-C₄alkyl) and C₁-C₆alkyl, thelatter two groups being optionally substituted by one or more fluoroatoms.
 2. The compound as claimed in claim 1 wherein R² is hydrogen andR¹ is fluoro or chloro.
 3. The compound as claimed in claim 1 wherein Xis *—SO₂NR³— wherein the bond marked with an asterisk is attached toAr¹.
 4. The compound as claimed in claim 1 wherein the radical Ar²SO₂—or Ar²N(R³)SO₂— is in the meta- or para-position of the ring Ar¹relative to the point of attachment of Ar¹ to the rest of the molecule.5. The compound as claimed in claim 1 wherein the radical Ar²SO₂— orAr²N(R³)SO₂— is in the ortho-position of the ring Ar¹ relative to thepoint of attachment of Ar¹ to the rest of the molecule.
 6. The compoundas claimed in claim 1 wherein Ar¹ is phenyl and Ar² is selected frompyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl andpyrazinyl.
 7. The compound as claimed in claim 1 wherein Ar¹ is selectedfrom furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, andpyrazinyl, and Ar² is phenyl.
 8. The compound as claimed in claim 1wherein when ring Ar¹ is heteroaryl it is selected from thienyl,pyridinyl, pyrimidinyl, thiazolyl, isothiazolyl and imidazolyl.
 9. Thecompound as claimed in claim 1 wherein when ring Ar² is heteroaryl it isselected from thienyl, pyridinyl, and pyrimidinyl.
 10. The compound asclaimed in claim 1 wherein optional substituents in Ar¹ and Ar² areselected from chloro, fluoro, —CN and methyl.
 11. The compound asclaimed in claim 1 which is the subject of any of the Examples herein,or which is a pharmaceutically acceptable salt of the subject of any ofthe Examples herein.
 12. A pharmaceutical composition comprising acompound as claimed in claim 1 and a pharmaceutically acceptablecarrier.